title: Linking cell surface receptors to microtubules: tubulin folding cofactor D mediates Dscam functions during neuronal morphogenesis.
abstract: Formation of functional neural networks requires the coordination of cell surface receptors and downstream signaling cascades, which eventually leads to dynamic remodeling of the cytoskeleton. Although a number of guidance receptors affecting actin cytoskeleton remodeling have been identified, it is relatively unknown how microtubule dynamics are regulated by guidance receptors. We used Drosophila olfactory projection neurons to study the molecular mechanisms of neuronal morphogenesis. Dendrites of each projection neuron target a single glomerulus of ∼50 glomeruli in the antennal lobe, and the axons show stereotypical pattern of terminal arborization. In the course of genetic analysis of the dachsous mutant allele (ds(UAO71)), we identified a mutation in the tubulin folding cofactor D gene (TBCD) as a background mutation. TBCD is one of five tubulin-folding cofactors required for the formation of α- and β-tubulin heterodimers. Single-cell clones of projection neurons homozygous for the TBCD mutation displayed disruption of microtubules, resulting in ectopic arborization of dendrites, and axon degeneration. Interestingly, overexpression of TBCD also resulted in microtubule disruption and ectopic dendrite arborization, suggesting that an optimum level of TBCD is crucial for in vivo neuronal morphogenesis. We further found that TBCD physically interacts with the intracellular domain of Down syndrome cell adhesion molecule (Dscam), which is important for neural development and has been implicated in Down syndrome. Genetic analyses revealed that TBCD cooperates with Dscam in vivo. Our study may offer new insights into the molecular mechanism underlying the altered neural networks in cognitive disabilities of Down syndrome.
authors: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan, and.
authors: Misako
authors: M
authors: Okumura
authors: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan, and.
authors: Chisako
authors: C
authors: Sakuma
authors: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, 102-0076, Japan.
authors: Masayuki
authors: M
authors: Miura
authors: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, 102-0076, Japan tchihara@mol.f.u-tokyo.ac.jp.
authors: Takahiro
authors: T
authors: Chihara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D004330:Drosophila / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D055495:Neurogenesis; D011485:Protein Binding; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; C491736:Dscam1 protein, Drosophila; D008869:Microtubule-Associated Proteins; C000596801:TBCD protein, Drosophila
keywords: Drosophila; Dscam; axon; dendrite; microtubule; tubulin
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