Secondary literature sources for FAS1

The following references were automatically generated.

Khare N, Fascetti N, DaRocha S, Chiquet-Ehrismann R, Baumgartner S
Expression patterns of two new members of the Semaphorin family in Drosophila suggest early functions during embryogenesis.
Mech Dev. 2000; 91: 393-7
Display abstract
We report the sequence and expression analysis of two new Drosophila members of the Semaphorin family. Both proteins show the presence of Semaphorin domains and transmembrane domains. Both genes are expressed maternally and in embryos, and reveal distinct expression patterns much earlier than the onset of neurogenesis. We also present an overview of the domain structure of all so far known semaphorins in Drosophila. Furthermore, we compared all Drosophila and C. elegans Semaphorins and discuss them in the light of their evolution.

Klostermann A, Lutz B, Gertler F, Behl C
The orthologous human and murine semaphorin 6A-1 proteins (SEMA6A-1/Sema6A-1) bind to the enabled/vasodilator-stimulated phosphoprotein-like protein (EVL) via a novel carboxyl-terminal zyxin-like domain.
J Biol Chem. 2000; 275: 39647-53
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Neuronal development and apoptosis critically depend on the transformation of extracellular signals to intracellular actions resulting in cytoskeletal rearrangements. Ena/VASP (enabled/vasodilator-stimulated phosphoprotein) proteins play an important role in actin and filament dynamics, whereas members of the semaphorin protein family are guidance signals in embryo- and organogenesis. Here, we report the identification of two novel transmembranous human and murine semaphorins, (HSA)SEMA6A-1 and (MMU)Sema6A-1. These semaphorin 6 variants directly link the Ena/VASP and the semaphorin protein family, since SEMA6A-1/Sema6A-1 is capable of a selective binding to the protein EVL (Ena/VASP-like protein). EVL is the third member of the Ena/VASP family of proteins that was identified sharing the same structural features as Mena (mammalian enabled) and VASP, although its functionality seems to be different from that of the other members. Here we demonstrate that SEMA6A-1/Sema6A-1 is colocalized with EVL via its zyxin-like carboxyl-terminal domain that contains a modified binding motif, which further stresses the existence of functional differences between EVL and Mena/VASP. In addition these findings suggest a completely new role for transmembranous semaphorins such as SEMA6A-1/Sema6A-1 in retrograde signaling.

Reynolds WS, Schwarz JA, Weis VM
Symbiosis-enhanced gene expression in cnidarian-algal associations: cloning and characterization of a cDNA, sym32, encoding a possible cell adhesion protein.
Comp Biochem Physiol A Mol Integr Physiol. 2000; 126: 33-44
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Mutualistic endosymbioses between two partners are complex associations that are regulated by the genetic interactions of the partners. One important marine symbiosis is that between various cnidarians, such as corals and anemones, and their photosynthetic algal symbionts. We have been interested in characterizing cnidarian host genes that are expressed as a function of the symbiotic state, using the temperate sea anemone Anthopleura elegantissima as a model. In this study, we report on symbiosis-enhanced expression and synthesis of sym32 in anemones. We characterized the full-length sym32 cDNA, obtained by RT-PCR, and demonstrated, by semi-quantitative RT-PCR, that sym32 transcript was much more abundant in symbiotic than in non-symbiotic host anemone RNA. Further, using immunoblots, we determined that an antibody made to a sym32 fusion protein labeled a 32 kD band much more strongly in symbiotic compared to non-symbiotic anemone protein homogenates. Databank searches revealed that the sym32 deduced amino acid sequence shares significant homology with the fasciclin I (Fas I) family of homophilic cell adhesion proteins, present in a variety of organisms ranging from bacteria to humans. This strong homology with the Fas I family suggests that sym32 is involved in regulation of the symbiosis by mediating cell-cell interactions.

Schultz CJ, Johnson KL, Currie G, Bacic A
The classical arabinogalactan protein gene family of arabidopsis.
Plant Cell. 2000; 12: 1751-68
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Arabinogalactan proteins (AGPs) are extracellular proteoglycans implicated in plant growth and development. We searched for classical AGPs in Arabidopsis by identifying expressed sequence tags based on the conserved domain structure of the predicted protein backbone. To confirm that these genes encoded bona fide AGPs, we purified native AGPs and then deglycosylated and deblocked them for N-terminal protein sequencing. In total, we identified 15 genes encoding the protein backbones of classical AGPs, including genes for AG peptides-AGPs with very short backbones (10 to 13 amino acid residues). Seven of the AGPs were verified as AGPs by protein sequencing. A gene encoding a putative cell adhesion molecule with AGP-like domains was also identified. This work provides a firm foundation for beginning functional analysis by using a genetic approach.

Schmucker D et al.
Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity.
Cell. 2000; 101: 671-84
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A Drosophila homolog of human Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin superfamily member, was isolated by its affinity to Dock, an SH3/SH2 adaptor protein required for axon guidance. Dscam binds directly to both Dock's SH2 and SH3 domains. Genetic studies revealed that Dscam, Dock and Pak, a serine/threonine kinase, act together to direct pathfinding of Bolwig's nerve, containing a subclass of sensory axons, to an intermediate target in the embryo. Dscam also is required for the formation of axon pathways in the embryonic central nervous system. cDNA and genomic analyses reveal the existence of multiple forms of Dscam with a conserved architecture containing variable Ig and transmembrane domains. Alternative splicing can potentially generate more than 38,000 Dscam isoforms. This molecular diversity may contribute to the specificity of neuronal connectivity.

Rich T, Allen R, Trowsdale J
How low can toll go?
Trends Genet. 2000; 16: 292-4

Sanchez D, Ganfornina MD, Torres-Schumann S, Speese SD, Lora JM, Bastiani MJ
Characterization of two novel lipocalins expressed in the Drosophila embryonic nervous system.
Int J Dev Biol. 2000; 44: 349-59
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We have found two novel lipocalins in the fruit fly Drosophila melanogaster that are homologous to the grasshopper Lazarillo, a singular lipocalin within this protein family which functions in axon guidance during nervous system development. Sequence analysis suggests that the two Drosophila proteins are secreted and possess peptide regions unique in the lipocalin family. The mRNAs of DNLaz (for Drosophila neural Lazarillo) and DGLaz (for Drosophila glial Lazarillo) are expressed with different temporal patterns during embryogenesis. They show low levels of larval expression and are highly expressed in pupa and adult flies. DNLaz mRNA is transcribed in a subset of neurons and neuronal precursors in the embryonic CNS. DGLaz mRNA is found in a subset of glial cells of the CNS: the longitudinal glia and the medial cell body glia. Both lipocalins are also expressed outside the nervous system in the developing gut, fat body and amnioserosa. The DNLaz protein is detected in a subset of axons in the developing CNS. Treatment with a secretion blocker enhances the antibody labeling, indicating the DNLaz secreted nature. These findings make the embryonic nervous system expression of lipocalins a feature more widespread than previously thought. We propose that DNLaz and DGLaz may have a role in axonal outgrowth and pathfinding, although other putative functions are also discussed.

Fox GL, Rebay I, Hynes RO
Expression of DFak56, a Drosophila homolog of vertebrate focal adhesion kinase, supports a role in cell migration in vivo.
Proc Natl Acad Sci U S A. 1999; 96: 14978-83
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Focal adhesion kinase (FAK) is a highly conserved, cytoplasmic tyrosine kinase that has been implicated in promoting cell migration and transmission of antiapoptotic signals in vertebrate cells. In cultured cells, integrin engagement with the extracellular matrix promotes the recruitment of FAK to focal contacts and increases in its phosphotyrosine content and kinase activity, suggesting FAK is an intracellular mediator of integrin signaling. We have identified a Drosophila FAK homolog, DFak56, that is 33% identical to vertebrate FAK, with the highest degree of homology in domains critical for FAK function, including the kinase and focal adhesion targeting domains, and several protein-protein interaction motifs. Furthermore, when expressed in NIH 3T3 cells, DFak56 both localizes to focal contacts and displays the characteristic elevation of phosphotyrosine content in response to plating the cells on fibronectin. During embryogenesis, DFak56 is broadly expressed, and it becomes elevated in the gut and central nervous system at later stages. Consistent with a role in cell migration, we also observe that DFak56 is abundant in the border cells of developing egg chambers before the onset of, and during, their migration.

Ouyang P
Antibodies differentiate desmosome-form and nucleus-form pinin: evidence that pinin is a moonlighting protein with dual location at the desmosome and within the nucleus.
Biochem Biophys Res Commun. 1999; 263: 192-200
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Pinin is a desmosome-associated protein occurring in epithelia, cardiac muscle, and meninges. This molecule was found to be capable of enhancing cell junction formation and thought to play a key role in reorganization and stabilization of the desmosome-intermediate filament complex in epithelial cells (J. Cell Biol. (1996) 135, 1027-1042). Recently a protein, claimed to be localized exclusively in the nucleus, however, with amino acid sequence identical to pinin, was reported (E. J. Cell Biol. (1998) 75, 295-298). Here I present evidence that pinin exists simultaneously at the desmosome and within the nucleus by generating location-specific monoclonal antibodies. Although the desmosome-form (d-form) and the nucleus-form (n-form) pinin share identical amino acid sequences as demonstrated by cDNA library screening and DNA sequencing, they exhibit remarkably different biochemical properties, reflecting the apparent different multiprotein nature of their differential cellular locations. In addition, the d-form pinin is characterized by a dynamic transport process which involves the gradual diminishing of nuclear materials relative to enhanced anchoring of pinin to the desmosome upon mature cells. Finally I demonstrate that pinin exists in two forms of different gene product: pinin1 and pinin2. These data argue strongly against the statement that pinin is an exclusive nuclear protein and support the notion that pinin is a moonlighting protein with more than one function as a consequence of its dual cellular location.

Funatsu N et al.
Characterization of a novel rat brain glycosylphosphatidylinositol-anchored protein (Kilon), a member of the IgLON cell adhesion molecule family.
J Biol Chem. 1999; 274: 8224-30
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In the central nervous system, many cell adhesion molecules are known to participate in the establishment and remodeling of the neural circuit. Some of the cell adhesion molecules are known to be anchored to the membrane by the glycosylphosphatidylinositol (GPI) inserted to their C termini, and many GPI-anchored proteins are known to be localized in a Triton-insoluble membrane fraction of low density or so-called "raft." In this study, we surveyed the GPI-anchored proteins in the Triton-insoluble low density fraction from 2-week-old rat brain by solubilization with phosphatidylinositol-specific phospholipase C. By Western blotting and partial peptide sequencing after the deglycosylation with peptide N-glycosidase F, the presence of Thy-1, F3/contactin, and T-cadherin was shown. In addition, one of the major proteins, having an apparent molecular mass of 36 kDa after the peptide N-glycosidase F digestion, was found to be a novel protein. The result of cDNA cloning showed that the protein is an immunoglobulin superfamily member with three C2 domains and has six putative glycosylation sites. Since this protein shows high sequence similarity to IgLON family members including LAMP, OBCAM, neurotrimin, CEPU-1, AvGP50, and GP55, we termed this protein Kilon (a kindred of IgLON). Kilon-specific monoclonal antibodies were produced, and Western blotting analysis showed that expression of Kilon is restricted to brain, and Kilon has an apparent molecular mass of 46 kDa in SDS-polyacrylamide gel electrophoresis in its expressed form. In brain, the expression of Kilon is already detected in E16 stage, and its level gradually increases during development. Kilon immunostaining was observed in the cerebral cortex and hippocampus, in which the strongly stained puncta were observed on dendrites and soma of pyramidal neurons.

Lekven AC, Tepass U, Keshmeshian M, Hartenstein V
faint sausage encodes a novel extracellular protein of the immunoglobulin superfamily required for cell migration and the establishment of normal axonal pathways in the Drosophila nervous system.
Development. 1998; 125: 2747-58
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We examined the structure of the nervous system in Drosophila embryos homozygous for a null mutation in the faint sausage (fas) gene. In the peripheral nervous system (PNS) of fas mutants, neurons fail to delaminate from the ectodermal epithelium; in the central nervous system (CNS), the positions of neuronal cell bodies and glial cells are abnormal and normal axonal pathways do not form. Sequence analysis of fas cDNAs revealed that the fas protein product has characteristics of an extracellular protein and that it is a novel member of the immunoglobulin (Ig) superfamily. In situ hybridization demonstrated that fas transcripts are expressed throughout the embryo but they are in relatively high concentrations in the lateral ectoderm, from which the peripheral nervous system delaminates and in the CNS. Antiserum directed against Fas protein was found to stain neurons but not glia in the CNS. We conclude that fas encodes a protein that, in the developing nervous system, is present on the surface of neurons and is essential for nerve cell migration and the establishment of axonal pathways.

Kim J et al.
Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing.
Proc Natl Acad Sci U S A. 1998; 95: 12364-9
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The glial cells missing (gcm) gene in Drosophila encodes a transcription factor that determines the choice between glial and neuronal fates. We report here the isolation of two mammalian gcm homologs, Gcm1 and Gcm2, and the characterization of their expression patterns during embryonic development. Although Gcm2 is expressed in neural tissues at a low level, the major sites of expression for both of the mammalian genes are nonneural, suggesting that the functions of the mammalian homologs have diverged and diversified. However, when expressed ectopically, Gcm1 can substitute functionally for Drosophila gcm by transforming presumptive neurons into glia. Thus, certain biochemical properties, although not the specificity of the tissue in which the gene is expressed, have been conserved through the evolution of the Gcm gene family.

Dye CA, Lee JK, Atkinson RC, Brewster R, Han PL, Bellen HJ
The Drosophila sanpodo gene controls sibling cell fate and encodes a tropomodulin homolog, an actin/tropomyosin-associated protein.
Development. 1998; 125: 1845-56
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Notch signaling is required in many invertebrate and vertebrate cells to promote proper cell fate determination. Mutations in sanpodo cause many different neuronal peripheral nervous system precursor cells to generate two identical daughter neurons, instead of a neuron and sibling cell. This phenotype is similar to that observed when Notch function is lost late in embryonic development and opposite to the numb loss-of-function phenotype. Genetic interaction studies show that sanpodo is epistatic to numb. sanpodo encodes a homolog of tropomodulin, an actin/tropomyosin-associated protein. Loss of sanpodo leads to an aberrant F-actin distribution and causes differentiation defects of actin-containing sensory structures. Our data suggest that an actin-based process is involved in Notch signaling.

Suzuki N et al.
A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin and may be involved in trophinin-mediated cell adhesion between trophoblast and endometrial epithelial cells.
Proc Natl Acad Sci U S A. 1998; 95: 5027-32
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Trophinin and tastin form a cell adhesion molecule complex that potentially mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of implantation. Trophinin and tastin, however, do not directly bind to each other, suggesting the presence of an intermediary protein. The present study identifies a cytoplasmic protein, named bystin, that directly binds trophinin and tastin. Bystin consists of 306 amino acid residues and is predicted to contain tyrosine, serine, and threonine residues in contexts conforming to motifs for phosphorylation by protein kinases. Database searches revealed a 53% identity of the predicted peptide sequence with the Drosophila bys (mrr) gene. Direct protein-protein interactions of trophinin, tastin, and bystin analyzed by yeast two-hybrid assays and by in vitro protein binding assays indicated that binding between bystin and trophinin and between bystin and tastin is enhanced when cytokeratin 8 and 18 are present as the third molecule. Immunocytochemistry of bystin showed that bystin colocalizes with trophinin, tastin, and cytokeratins in a human trophoblastic teratocarcinoma cell, HT-H. It is therefore possible that these molecules form a complex and thus are involved in the process of embryo implantation.

Kim HS, Chen Y, Lonai P
Complex regulation of multiple cytohesin-like genes in murine tissues and cells.
FEBS Lett. 1998; 433: 312-6
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Three cytohesin-like cDNA molecules were isolated from murine ES cell derived embryoid bodies. The genomic structure of one of the three, CLM2, has been determined and transcriptional variants of each were isolated from a mouse brain cDNA library. The relative expression patterns of CLM1, 2, 3 and their transcriptional alternatives were determined by RT-PCR, nucleotide sequencing and RNA blotting. Their broad distribution and cell and tissue specific expression patterns suggest complex regulation during development and in the adult.

Hortsch M et al.
Structural requirements for outside-in and inside-out signaling by Drosophila neuroglian, a member of the L1 family of cell adhesion molecules.
J Cell Biol. 1998; 142: 251-61
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Expression of the Drosophila cell adhesion molecule neuroglian in S2 cells leads to cell aggregation and the intracellular recruitment of ankyrin to cell contact sites. We localized the region of neuroglian that interacts with ankyrin and investigated the mechanism that limits this interaction to cell contact sites. Yeast two-hybrid analysis and expression of neuroglian deletion constructs in S2 cells identified a conserved 36-amino acid sequence that is required for ankyrin binding. Mutation of a conserved tyrosine residue within this region reduced ankyrin binding and extracellular adhesion. However, residual recruitment of ankyrin by this mutant neuroglian molecule was still limited to cell contacts, indicating that the lack of ankyrin binding at noncontact sites is not caused by tyrosine phosphorylation. A chimeric molecule, in which the extracellular domain of neuroglian was replaced with the corresponding domain from the adhesion molecule fasciclin II, also selectively recruited ankyrin to cell contacts. Thus, outside-in signaling by neuroglian in S2 cells depends on extracellular adhesion, but does not depend on any unique property of its extracellular domain. We propose that the recruitment of ankyrin to cell contact sites depends on a physical rearrangement of neuroglian in response to cell adhesion, and that ankyrin binding plays a reciprocal role in stabilizing the adhesive interaction.

Tear G, Harris R, Sutaria S, Kilomanski K, Goodman CS, Seeger MA
commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein.
Neuron. 1996; 16: 501-14
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The commissureless (comm) gene was identified previously in a large-scale screen for mutations that disrupt CNS axon pathways in Drosophila. The comm gene has a unique mutant phenotype: the complete absence of most axon commissures, while midline cells and other aspects of CNS fate and patterning are left unchanged. Here, we report on the molecular cloning, characterization, and expression of the comm gene. comm encodes a novel protein of 370 amino acids that lacks a signal sequence, has a transmembrane domain, and biochemically copurifies with membranes. COMM mRNA and COMM protein are dynamically expressed during embryogenesis, including by CNS midline glia during the formation of the axon commissures. Anti-COMM antibodies reveal strong staining of organelles likely to include the Golgi complex and endosomes and weaker staining of the cell surface. As commissural growth cones contact and traverse the CNS midline, COMM protein is apparently transferred from midline glia to commissural axons.

Mitchell KJ et al.
Genetic analysis of Netrin genes in Drosophila: Netrins guide CNS commissural axons and peripheral motor axons.
Neuron. 1996; 17: 203-15
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Two tandem Netrin genes in Drosophila are expressed at the midline of the developing CNS and in different subsets of neurons, muscles, and epidermal patches. In embryos carrying a small deficiency that deletes both genes, CNS axon commissures are partially missing or thinner. This phenotype is rescued by expressing either Netrin gene at the midline. Pan-neural expression of either gene causes disruption of commissural and longitudinal tracts, indicating that the pattern of Netrin expression is crucial and that Netrins function as instructive cues. The double mutant also shows defects in motor axon projections. Expression of either Netrin gene in all muscles also results in aberrant motor projections. Thus, Drosophila Netrins are required for the guidance of commissural axons at the midline, and of motor axons to their target muscles.

Zhang SD, Kassis J, Olde B, Mellerick DM, Odenwald WF
Pollux, a novel Drosophila adhesion molecule, belongs to a family of proteins expressed in plants, yeast, nematodes, and man.
Genes Dev. 1996; 10: 1108-19
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Adhesion molecules have pivotal roles in cellular processes critical to the development and maintenance of multicellular organisms. Here we describe a new member of the adhesive repertoire encoded by the Drosophila pollux (plx) gene. Marked by a novel 74-amino-acid domain, Plx belongs to a highly conserved family with members in plants, yeast, nematodes, and man, including the human oncoprotein TRE17. Essential for viability, plx mutant analysis indicates that larval death is attributable to asphyxiation brought on by fluid-congested tracheal tubes. Ultrastructural examination of mutant tracheae reveals defects in cell-extracellular matrix contacts. During embryogenesis, Plx uniformly covers the apical surface of cellular blastoderm cells. It is later found regionally concentrated along subsets of central nervous system axon pathways and on the apical surface of the trachea's tubular epithelium. Cell attachment assays demonstrate that Plx can serve as a ligand for cell surface integrins. Plx also contains a motor neuron-selective adhesive site, multiple proteoglycan-binding motifs, and a leucine zipper: all suggest possible associations with additional components of the adhesion complex.

Hortsch M, Wang YM, Marikar Y, Bieber AJ
The cytoplasmic domain of the Drosophila cell adhesion molecule neuroglian is not essential for its homophilic adhesive properties in S2 cells.
J Biol Chem. 1995; 270: 18809-17
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Drosophila neuroglian is a transmembrane glycoprotein that has strong structural and sequence homology to the vertebrate L1 gene family of cell adhesion molecules (Bieber, A.J., Snow, P.M., Hortsch, M., Patel, N.H., Jacobs, J.R., Traquina, Z.R., Schilling, J., and Goodman, C.S. (1989) Cell 59, 447-460. Two different neuroglian protein forms that are generated by a differential splicing process are expressed in a tissue-specific fashion by embryonic and larval cells (Hortsch, M., Bieber, A.J., Patel, N.H., and Goodman, C.S. (1990) Neuron 4, 697-709). The two neuroglial polypeptides differ only in their cytoplasmic domains. Both of these neuroglian species, when transfected into the expressed in Drosophila S2 cells, induce the calcium-independent, homophilic aggregation of transformed cells. A third artificial neuroglian protein form was constructed by substituting the neuroglian transmembrane segment and cytoplasmic domains with the glycosyl phosphatidylinositol attachment signal of the Drosophila fasciclin I protein. This cDNA construct generates a glycosyl phosphatidylinositol-anchored form of neuroglian, which retains the ability to induce homophilic cell aggregation when expressed in S2 cells, and was able to interact with both of the two naturally occurring neuroglian polypeptides. These results demonstrate that neuroglian mediates a calcium-independent, homophilic cell adhesion activity and that neither cytoplasmic neuroglian domains nor a direct interaction with cytoskeletal elements is essential for this property.

Zhong Y, Shanley J
Altered nerve terminal arborization and synaptic transmission in Drosophila mutants of cell adhesion molecule fasciclin I.
J Neurosci. 1995; 15: 6679-87
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This work investigates the role of cell adhesion molecules in development of synaptic connections and functions through a genetic approach. Fasciclin I (Fas I) is an insect glycoprotein capable of mediating homophilic cell adhesion. It has been shown that Fas I is expressed in motor nerve axons and terminals that innervate larval body-wall muscles in Drosophila. Immunohistochemical analysis of these motor nerve terminals has revealed that nerve terminal arborization, quantified by the numbers of the nerve terminal branches and varicosities, is enhanced in the null mutant fas ITE. In contrast, the number of branches and varicosities are reduced in larvae that overexpress the Fas I molecule resulting from additional copies of the fas I transgene in P(fas I+) or the chromosome duplication in Dp(fas I) mutants. Although arborization is altered, the overall stereotypical pattern of nerve terminal innervation of the body-wall muscle fibers is preserved in all the Fas I mutants examined. The voltage-clamp analysis of excitatory junctional currents (ejcs) at the neuromuscular junction indicates that the amplitude of ejcs is reduced in fas ITE, but increased in P(fas I+) and Dp(fas I) compared to that in wild-type larvae. Further electrophysiological analysis shows that the quantal content and the evoked frequency-dependent response are affected in these mutants, indicating a defective presynaptic function in addition to the anatomic abnormality. Therefore, the cell adhesion molecule Fas I may not be essential for target recognition and synaptogenesis at the larval neuromuscular junction, but may play a role in fine-turning nerve terminal arborization and possibly in modifying, directly or indirectly, development of presynaptic functions.

Castonguay LA, Bryant SH, Snow PM, Fetrow JS
A proposed structural model of domain 1 of fasciclin III neural cell adhesion protein based on an inverse folding algorithm.
Protein Sci. 1995; 4: 472-83
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Fasciclin III is an integral membrane protein expressed on a subset of axons in the developing Drosophila nervous system. It consists of an intracellular domain, a transmembrane region, and an extracellular region composed of three domains, each predicted to form an immunoglobulin-like fold. The most N-terminal of these domains is expected to be important in mediating cell-cell recognition events during nervous system development. To learn more about the structure/function relationships in this cellular recognition molecule, a model structure of this domain was built. A sequence-to-structure alignment algorithm was used to align the protein sequence of the fasciclin III first domain to the immunoglobulin McPC603 structure. Based on this alignment, a model of the domain was built using standard homology modeling techniques. Side-chain conformations were automatically modeled using a rotamer search algorithm and the model was minimized to relax atomic overlaps. The resulting model is compact and has chemical characteristics consistent with related globular protein structures. This model is a de novo test of the sequence-to-structure alignment algorithm and is currently being used as the basis for mutagenesis experiments to discern the parts of the fasciclin III protein that are necessary for homophilic molecular recognition in the developing Drosophila nervous system.

Baumgartner S, Chiquet-Ehrismann R
Tena, a Drosophila gene related to tenascin, shows selective transcript localization.
Mech Dev. 1993; 40: 165-76
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We report the identification and molecular characterization of tena*, a Drosophila gene located at 11A6-9 on the X-chromosome. The deduced protein of 782 amino acids contains eight tenascin-type EGF-like repeats not described in Drosophila before, but lacks the fibronectin type III repeats and the fibrinogen homology present in the vertebrate tenascin molecules. Tena codes for a large transcript which exhibits extremely long 5' and 3' untranslated regions. Tena transcripts show a specific perinuclear localization within cells and are mainly expressed in the central nervous system, in the brain and near muscle attachment sites during embryogenesis. During pupal stages, tena is detected in the eye. These expression patterns are reminiscent of those of vertebrate tenascin. Tenascin-type EGF-like sequences are also detected in other loci of Drosophila and in various other organisms, indicating the existence of a family of genes related to tenascin.

Wang WC, Zinn K, Bjorkman PJ
Expression and structural studies of fasciclin I, an insect cell adhesion molecule.
J Biol Chem. 1993; 268: 1448-55
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Fasciclin I is a lipid-linked cell-surface glycoprotein that can act as a homophilic adhesion molecule in tissue culture cells. It is thought to be involved in growth cone guidance in the embryonic insect nervous system. To facilitate structure-function studies, we have generated Chinese hamster ovary (CHO) cell lines expressing high levels of cell surface grasshopper and Drosophila fasciclin I. Grasshopper fasciclin I released by phospholipase C cleavage was purified on an immunoaffinity column and single crystals were obtained that diffracted to approximately 5-A resolution. We also generated CHO and Drosophila S2 cell lines that produce a secreted form of fasciclin I. Fasciclin I expressed in S2 cells contains significantly less carbohydrate than the protein expressed in CHO cells, and may therefore be more suitable for crystallization. Biochemical characterization of purified fasciclin I indicates that the extracellular portion exists as a monomer in solution. Circular dichroism studies suggest that fasciclin I is primarily alpha-helical. Its structure is therefore different from other known cell adhesion molecules, which are predicted to be elongated beta-sheet structures. This suggests that fasciclin I may define a new structural motif used to mediate adhesive interactions between cell surfaces.

Fetrow JS, Bryant SH
New programs for protein tertiary structure prediction.
Biotechnology (N Y). 1993; 11: 479-84
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Prediction of protein tertiary structure remains an unsolved problem in molecular biology, but a solution to this problem is extremely important for protein engineering and rational drug design. Recent developments in motif recognition and side chain modeling present the prospect of nearly automatic model building for a large fraction of newly determined protein sequences. We review some of these new algorithms and present preliminary results of their application to the prediction of a structure for fasciclin III, a neural adhesion molecule from Drosophila.

McAllister L, Rehm EJ, Goodman GS, Zinn K
Alternative splicing of micro-exons creates multiple forms of the insect cell adhesion molecule fasciclin I.
J Neurosci. 1992; 12: 895-905
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Fasciclin I is a homophilic cell adhesion molecule in insects that is dynamically expressed on a subset of axon pathways in the embryonic nervous system, and on a variety of other cells and tissues during development. The fasciclin I protein consists of four homologous 150 amino acid domains. In this article, we describe the complete sequence of the Drosophila fasciclin I (fasI) gene. The gene consists of 15 exons and is distributed over 14 kilobases of DNA. We examine the structure and temporal expression pattern of multiple fasciclin I mRNAs that differ in the lengths of their 3' untranslated regions. We also show that a highly conserved sequence at the end of the second domain can be altered by the addition of three or six amino acids that are encoded by two alternatively spliced 9 base pair (bp) micro-exons. In grasshopper fasciclin I mRNAs, there are 9 bp and 6 bp insertions at the same position. The first of these insertions is identical in sequence to the first fly micro-exon. The grasshopper insertions are not found together in the same mRNA, so grasshopper fasciclin I species differ by the addition of three or two extra amino acids to the second domain. The alternatively spliced mRNAs are differentially expressed during embryogenesis, and all three of them are present in nerve cord preparations. We suggest that the amino acids inserted by alternative micro-exon splicing may alter the binding specificity of fasciclin I.

Pulido D, Campuzano S, Koda T, Modolell J, Barbacid M
Dtrk, a Drosophila gene related to the trk family of neurotrophin receptors, encodes a novel class of neural cell adhesion molecule.
EMBO J. 1992; 11: 391-404
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We report the identification and molecular characterization of Dtrk, a Drosophila gene encoding a receptor tyrosine kinase highly related to the trk family of mammalian neurotrophin receptors. The product of the Dtrk gene, gp160Dtrk, is dynamically expressed during Drosophila embryogenesis in several areas of the developing nervous system, including neurons and fasciculating axons. gp160Dtrk has structural homology with neural cell adhesion molecules of the immunoglobulin superfamily and promotes cell adhesion in a homophilic, Ca2+ independent manner. More importantly, this adhesion process specifically activates its tyrosine protein kinase activity. These findings suggest that gp160Dtrk represents a new class of neural cell adhesion molecules that may regulate neuronal recognition and axonal guidance during the development of the Drosophila nervous system.

McAllister L, Goodman CS, Zinn K
Dynamic expression of the cell adhesion molecule fasciclin I during embryonic development in Drosophila.
Development. 1992; 115: 267-76
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A number of different cell surface glycoproteins expressed in the central nervous system (CNS) have been identified in insects and shown to mediate cell adhesion in tissue culture systems. The fasciclin I protein is expressed on a subset of CNS axon pathways in both grasshopper and Drosophila. It consists of four homologous 150-amino acid domains which are unrelated to other sequences in the current databases, and is tethered to the cell surface by a glycosyl-phosphatidylinositol linkage. In this paper we examine in detail the expression of fasciclin I mRNA and protein during Drosophila embryonic development. We find that fasciclin I is expressed in several distinct patterns at different stages of development. In blastoderm embryos it is briefly localized in a graded pattern. During the germ band extended period its expression evolves through two distinct phases. Fasciclin I mRNA and protein are initially localized in a 14-stripe pattern which corresponds to segmentally repeated patches of neuroepithelial cells and neuroblasts. Expression then becomes confined to CNS and peripheral sensory (PNS) neurons. Fasciclin I is expressed on all PNS neurons, and this expression is stably maintained for several hours. In the CNS, fasciclin I is initially expressed on all commissural axons, but then becomes restricted to specific axon bundles. The early commissural expression pattern is not observed in grasshopper embryos, but the later bundle-specific pattern is very similar to that seen in grasshopper. The existence of an initial phase of expression on all commissural bundles helps to explain the loss-of-commissures phenotype of embryos lacking expression of both fasciclin I and of the D-abl tyrosine kinase. Fasciclin I is also expressed in several nonneural tissues in the embryo.

Grenningloh G, Rehm EJ, Goodman CS
Genetic analysis of growth cone guidance in Drosophila: fasciclin II functions as a neuronal recognition molecule.
Cell. 1991; 67: 45-57
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fasiclin II (fas II), a member of the immunoglobulin superfamily, was previously characterized and cloned in grasshopper. To analyze the function of this molecule, we cloned the Drosophila fas II homolog and generated mutants in the gene. In both grasshopper and Drosophila, fasciclin II is expressed on the MP1 fascicle and a subset of other axon pathways. In fas II mutant Drosophila embryos, the CNS displays no gross phenotype, but the MP1 fascicle fails to develop. The MP1, dMP2, and vMP2 growth cones fail to recognize one another or other axons that normally join the MP1 pathway. During their normal period of axon out-growth, these growth cones stall and do not join any other neighboring pathway. Thus, fasciclin II functions as a neuronal recognition molecule for the MP1 axon pathway. These studies serve as molecular confirmation for the existence of functional labels on specific axon pathways in the developing nervous system.

Hlavin ML, Lemmon V
Molecular structure and functional testing of human L1CAM: an interspecies comparison.
Genomics. 1991; 11: 416-23
Display abstract
The rodent, avian, and insect L1-like cell adhesion molecules are members of the immunoglobulin superfamily that have been implicated in axon growth. We have isolated an L1-like molecule from human brain and found that it also supports neurite growth in vitro. We have also cloned and sequenced the entire coding region of human L1CAM and found that it shows a very high degree of homology to mouse L1cam, with 92% identity at the amino acid level. This similarity suggests that L1CAM is an important molecule in normal human nervous system development and nerve regeneration. Overall, there is substantially less homology to chick Ng-CAM; they are 40% identical at the amino acid level but many regions are highly conserved. Comparison of the sequences from human, mouse, chick, and Drosophila indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 are strongly conserved and thus are likely functionally important.

Elkins T, Hortsch M, Bieber AJ, Snow PM, Goodman CS
Drosophila fasciclin I is a novel homophilic adhesion molecule that along with fasciclin III can mediate cell sorting.
J Cell Biol. 1990; 110: 1825-32
Display abstract
Fasciclin I is a membrane-associated glycoprotein that is regionally expressed on a subset of fasciculating axons during neuronal development in insects; it is expressed on apposing cell surfaces, suggesting a role in specific cell adhesion. In this paper we show that Drosophila fasciclin I is a novel homophilic cell adhesion molecule. When the nonadhesive Drosophila S2 cells are transfected with the fasciclin I cDNA, they form aggregates that are blocked by antisera against fasciclin I. When cells expressing fasciclin I are mixed with cells expressing fasciclin III, another Drosophila homophilic adhesion molecule, the mixture sorts into aggregates homogeneous for either fasciclin I- or fasciclin III-expressing cells. The ability of these two novel adhesion molecules to mediate cell sorting in vitro suggests that they might play a similar role during neuronal development.

Elkins T, Zinn K, McAllister L, Hoffmann FM, Goodman CS
Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations.
Cell. 1990; 60: 565-75
Display abstract
Drosophila fasciclin I is a homophilic cell adhesion molecule expressed in the developing embryo on the surface of a subset of fasciculating CNS axons, all PNS axons, and some nonneuronal cells. We have identified protein-null mutations in the fasciclin I (fas I) gene, and show that these mutants are viable and do not display gross defects in nervous system morphogenesis. The Drosophila Abelson (abl) proto-oncogene homolog encodes a cytoplasmic tyrosine kinase that is expressed during embryogenesis primarily in developing CNS axons; abl mutants show no gross defects in CNS morphogenesis. However, embryos doubly mutant for fas I and abl display major defects in CNS axon pathways, particularly in the commissural tracts where expression of these two proteins normally overlaps. The double mutant shows a clear defect in growth cone guidance; for example, the RP1 growth cone (normally fas I positive) does not follow its normal path across the commissure.

Finkelstein R, Smouse D, Capaci TM, Spradling AC, Perrimon N
The orthodenticle gene encodes a novel homeo domain protein involved in the development of the Drosophila nervous system and ocellar visual structures.
Genes Dev. 1990; 4: 1516-27
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The orthodenticle (otd) locus of Drosophila is required for embryonic development, and null mutations of otd cause defects in head development and segmental patterning. We show here that otd is necessary for the formation of the embryonic central nervous system (CNS). otd mutations result in the formation of an abnormal neuropil and in the disappearance of identified neurons associated with the midline of the CNS. In addition, otd is allelic to ocelliless (oc), a mutation that causes the deletion of the ocelli of the adult fly. We have identified a transcription unit corresponding to the otd locus and find that it is expressed early in a stripe near the anterior pole of the cellular blastoderm and later in the region of the CNS from which these neurons normally arise. The predicted otd protein contains a well-conserved homeo domain and is therefore likely to be a transcriptional regulator involved in specifying cell fate both in the embryonic CNS and in the ocelli.

Hortsch M, Bieber AJ, Patel NH, Goodman CS
Differential splicing generates a nervous system-specific form of Drosophila neuroglian.
Neuron. 1990; 4: 697-709
Display abstract
We recently described the characterization and cloning of Drosophila neuroglian, a member of the immunoglobulin superfamily. Neuroglian contains six immunoglobulin-like domains and five fibronectin type III domains and shows strong sequence homology to the mouse neural cell adhesion molecule L1. Here we show that the neuroglian gene generates at least two different protein products by tissue-specific alternative splicing. The two protein forms differ in their cytoplasmic domains. The long form is restricted to the surface of neurons in the CNS and neurons and some support cells in the PNS; in contrast, the short form is expressed on a wide range of other cells and tissues. Thus, whereas the mouse L1 gene appears to encode only one protein that functions largely as a neural cell adhesion molecule, its Drosophila homolog, the neuroglian gene, encodes at least two protein forms that may play two different roles, one as a neural cell adhesion molecule and the other as a more general cell adhesion molecule involved in other tissues and imaginal disc morphogenesis.

Hortsch M, Goodman CS
Drosophila fasciclin I, a neural cell adhesion molecule, has a phosphatidylinositol lipid membrane anchor that is developmentally regulated.
J Biol Chem. 1990; 265: 15104-9
Display abstract
Fasciclin I is a homophilic neural cell adhesion molecule which is regionally expressed on a subset of fasciculating axons in both the grasshopper and Drosophila embryo, suggesting a role in axonal recognition. It is also dynamically expressed on a variety of other embryonic tissues. Biochemical analysis of the fasciclin I glycoprotein from Drosophila embryonic membranes and Schneider 1 cells indicates that it is tightly associated with the lipid bilayer by a phosphatidylinositol lipid moiety. In Drosophila embryos a large fraction of fasciclin I protein has lost its membrane anchor. The ratio of this soluble form to the phosphatidylinositol-linked form changes during embryogenesis. We speculate that removal of the phosphatidylinositol lipid from the fasciclin I protein could be a mechanism to regulate its adhesive function.

Snow PM, Bieber AJ, Goodman CS
Fasciclin III: a novel homophilic adhesion molecule in Drosophila.
Cell. 1989; 59: 313-23
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Drosophila fasciclin III is an integral membrane glycoprotein that is expressed on a subset of neurons and fasciculating axons in the developing CNS, as well as in several other tissues during development. Here we report on the isolation of a full-length cDNA encoding an 80 kd form of fasciclin III. We have used this cDNA, under heat shock control, to transfect the relatively nonadhesive Drosophila S2 cell line. Examination of these transfected cells indicates that fasciclin III is capable of mediating adhesion in a homophilic, Ca2+-independent manner. Sequence analysis reveals that fasciclin III encodes a transmembrane protein with no significant homology to any known protein, including the previously characterized families of vertebrate cell adhesion molecules. The distribution of this adhesion molecule on subsets of fasciculating axons and growth cones during Drosophila development suggests that fasciclin III plays a role in growth cone guidance.

Bieber AJ et al.
Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1.
Cell. 1989; 59: 447-60
Display abstract
Drosophila neuroglian is an integral membrane glycoprotein that is expressed on a variety of cell types in the Drosophila embryo, including expression on a large subset of glial and neuronal cell bodies in the central and peripheral nervous systems and on the fasciculating axons that extend along them. Neuroglian cDNA clones were isolated by expression cloning. cDNA sequence analysis reveals that neuroglian is a member of the immunoglobulin superfamily. The extracellular portion of the protein consists of six immunoglobulin C2-type domains followed by five fibronectin type III domains. Neuroglian is closely related to the immunoglobulin-like vertebrate neural adhesion molecules and, among them, shows most extensive homology to mouse L1. Its homology to L1 and its embryonic localization suggest that neuroglian may play a role in neural and glial cell adhesion in the developing Drosophila embryo. We report here on the identification of a lethal mutation in the neuroglian gene.

Montell DJ, Goodman CS
Drosophila substrate adhesion molecule: sequence of laminin B1 chain reveals domains of homology with mouse.
Cell. 1988; 53: 463-73
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Laminin, a substrate adhesion molecule in vertebrates, is a large glycoprotein complex in basement membranes that promotes cell adhesion, cell migration, and neurite outgrowth. Here we report on the cloning of the genes encoding the three subunits of Drosophila laminin. Sequence analysis of cDNA clones encoding the Drosophila B1 chain reveals a multidomain structure similar to that of its mouse homolog. The Drosophila sequence has only 25% amino acid identity with the mouse sequence in domains I, II, and IV. However, in one of the putative collagen-binding regions (domain VI) and the two cysteine-rich domains of EGF-like repeats (domains III and V), the amino acid identity between these two evolutionarily distant species jumps to 55%. Moreover, the number, length, and unique amino acid sequences of each of the 13 EGF-like repeats are highly conserved between Drosophila and mouse, suggesting that each may serve a unique function in protein-protein interactions.

Zhao DB, Cote S, Jahnig F, Haller J, Jackle H
Zipper encodes a putative integral membrane protein required for normal axon patterning during Drosophila neurogenesis.
EMBO J. 1988; 7: 1115-9
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During the development of the central nervous system, Drosophila embryo axons become organized in a stereo-typed fasciculation pattern. We have found that the zipper (zip) gene, initially identified on the basis of a defective larval cuticle in zip mutant embryos, is possibly involved in the establishment or maintenance of the axon pattern during the late stages of neurogenesis. The zip wild-type gene is expressed in the developing nervous system. It codes for a putative integral membrane protein. Both the molecular features of zipper and its biological effect in the nervous system of mutants suggest that zipper is an essential component for cell surface interactions involved in axon patterning, and that the cuticle phenotype of zip mutants is dependent on the primary defects observed in the nervous system.