Axon Patterning Requires D N-cadherin, a Novel Neuronal Adhesion Receptor, in the Drosophila Embryonic CNS

Iwai, Yoshio; Usui, Tadao; Hirano, Shinji; Steward, Ruth; Takeichi, Masatoshi; Uemura, Tadashi

doi:10.1016/s0896-6273(00)80349-9

Cited by 275 publications

(96 citation statements)

References 81 publications

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“…Cadherins of similar size exist in Drosophila, but they lack EGF and laminin G domains such as the Dachsous protein (30), or the number of cadherin domains is lower as was shown for DN-cadherin which harbors only 18 cadherin repeats (31). The expression of ftl in tubular tissues resembles the expression of vertebrate Fat cadherins in cells adjacent to ventricular zones.…”

Section: Silencing Of Fat-like Transcript Impairs Tubular Tissue Formmentioning

confidence: 88%

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

Castillejo-López¹,

Arias²,

Baumgärtner³

2004

Journal of Biological Chemistry

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Fat cadherins constitute a subclass of the large cadherin family characterized by the presence of 34 cadherin motifs. To date, three mammalian Fat cadherins have been described; however, only limited information is known about the function of these molecules. In this paper, we describe the second fat cadherin in Drosophila, fat-like (ftl). We show that ftl is the true orthologue of vertebrate fat-like genes, whereas the previously characterized tumor suppressor cadherin, fat, is more distantly related as compared with ftl. Ftl is a large molecule of 4705 amino acids. It is expressed apically in luminal tissues such as trachea, salivary glands, proventriculus, and hindgut. Silencing of ftl results in the collapse of tracheal epithelia giving rise to breaks, deletions, and sac-like structures. Other tubular organs such as proventriculus, salivary glands, and hindgut are also malformed or missing. These data suggest that Ftl is required for morphogenesis and maintenance of tubular structures of ectodermal origin and underline its similarity in function to a reported lethal mouse knock-out of fat1 where glomerular epithelial processes collapse. Based on our results, we propose a model where Ftl acts as a spacer to keep tubular epithelia apart rather than the previously described adhesive properties of the cadherin superfamily.

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Section: Silencing Of Fat-like Transcript Impairs Tubular Tissue Formmentioning

confidence: 88%

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

Castillejo-López¹,

Arias²,

Baumgärtner³

2004

Journal of Biological Chemistry

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“…2B). Interestingly, a spacer sequence is also found between the first and second cadherin domains of DN-cadherin, a Drosophila neuronal adhesion receptor (21).…”

Section: Sequence Alignment and Phylogeny Of C-ret Extracellular Domamentioning

confidence: 99%

Molecular Modeling of the Extracellular Domain of the RET Receptor Tyrosine Kinase Reveals Multiple Cadherin-like Domains and a Calcium-binding Site

Anders¹,

Kjær²,

Ibáñez

2001

Journal of Biological Chemistry

129

104

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Using bioinformatic tools, mutagenesis, and binding studies, we have investigated the structural organization of the extracellular region of the RET receptor tyrosine kinase, a functional receptor for glial cell linederived neurotrophic factor (GDNF). Multiple sequence alignments of seven vertebrate sequences and one invertebrate RET sequence delineated four distinct N-terminal domains, each of about 110 residues, containing many of the consensus motifs of the cadherin fold. Based on these alignments and the crystal structures of epithelial and neural cadherins, we have generated molecular models of each of the four cadherin-like domains in the extracellular region of human RET. The modeled structures represent realistic models from both energetic and geometrical points of view and are consistent with previous observations gathered from biochemical analyses of the effects of Hirschsprung's disease mutations affecting the folding and stability of the RET molecule, as well as our own site-directed mutagenesis studies of RET cadherin-like domain 1. We have also investigated the role of Ca 2؉ in ligand binding by RET and found that Ca 2؉ions are required for RET binding to GDNF but not for GDNF binding to the GFR␣1 co-receptor. In agreement with these results, RET, but not GFR␣1, was found to bind Ca 2؉ directly. Our results indicate that the overall architecture of the extracellular region of RET is more closely related to cadherins than previously thought. The models of the cadherin-like domains of human RET represent valuable tools with which to guide future site-directed mutagenesis studies aimed at identifying residues involved in ligand binding and receptor activation.The RET receptor tyrosine kinase is an unusual receptor from many points of view. It cannot by itself bind its ligand, GDNF, 1 unless in a complex with another protein, the glycosyl phosphatidylinositol-anchored receptor GFR␣1 (1, 2). In contrast with other receptor tyrosine kinases, there appears to be only one RET homologue in all species investigated so far. All members of the GDNF ligand family utilize RET as a signal transducing receptor subunit, with specificity being determined by cooperation between RET and different members of the GFR␣ family of glycosyl phosphatidylinositol-anchored receptors (1, 2). Both gain-and loss-of-function mutations in the RET gene have been identified in human diseases. Mutations in RET of patients with multiple endocrine neuroplasias type 2A and 2B and familial medullary thyroid carcinoma induce constitutive activation of the RET tyrosine kinase and lead to congenital and sporadic cancers in neuroendocrine organs (3, 4). On the other hand, loss-of-function mutations in RET cause a dominant genetic disorder of neural crest development known as Hirschsprung's disease (HSCR), which results in the death of neurons in distal segments of the enteric nervous systems and colon aganglionosis (5).The extracellular region of the RET molecule is peculiar compared with that found in other receptor tyrosine kinases in that ...

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“…4 B and C). The laminin A-G domain is present in other cadherin-like proteins, such as fly Fat (17), and DN-cadherin (25), and sea urchin G-cadherin (26). This domain is also present in other neural proteins, such as laminin A, agrin, merosin, slit, crumbs, and neurexin.…”

Section: Genomic Organization Of Two Human Flamingo Genesmentioning

confidence: 99%

“…The fly DN-cadherin gene is required for axon patterning in the central nervous system (25). This gene encodes a cadherin protein containing 15 ectodomain repeats, two cysteine-rich segments (C-rich), two laminin A-G domains, a transmembrane domain, and a cytoplasmic domain.…”

Section: Genomic Organization Of Drosophila Dn-cadherin and De-cadherinmentioning

confidence: 99%

Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes

Wu¹

2000

Proceedings of the National Academy of Sciences

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Recent studies revealed a striking difference in the genomic organization of classic cadherin genes and one family of ''nonclassic cadherin'' genes designated protocadherins. Specifically, the DNA sequences encoding the ectodomain repeats of classic cadherins are interrupted by multiple introns. By contrast, all of the encoded ectodomains of each member of the protocadherin gene clusters are present in one large exon. To determine whether large ectodomain exons are a general feature of protocadherin genes we have investigated the genomic organization of several additional human protocadherin genes by using DNA sequence information in GenBank. These genes include protocadherin 12 (Pcdh12), an ortholog of the mouse vascular endothelial cadherin-2 gene; hFmi1 and hFmi2, homologs of the Drosophila planar cell polarity gene, flamingo; hFat2, a homolog of the Drosophila tumor suppressor gene fat; and the Drosophila DN-cadherin and DE-cadherin genes. Each of these genes was found to be a member of the protocadherin subfamily, based on amino acid sequence comparisons of their ectodomains. Remarkably, all of these protocadherin genes share a common feature: most of the genomic DNA sequences encoding their ectodomains are not interrupted by an intron. We conclude that the presence of unusually large exons is a characteristic feature of protocadherin genes.

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Axon Patterning Requires D N-cadherin, a Novel Neuronal Adhesion Receptor, in the Drosophila Embryonic CNS

Cited by 275 publications

References 81 publications

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

Molecular Modeling of the Extracellular Domain of the RET Receptor Tyrosine Kinase Reveals Multiple Cadherin-like Domains and a Calcium-binding Site

Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes

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