The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase.
The Down syndrome critical region (DSCR) on Chromosome 21 contains many genes whose duplication may lead to the major phenotypic features of Down syndrome and especially the associated mental retardation. However, the functions of DSCR genes are mostly unknown and their possible involvement in key brain developmental events still largely unexplored. In this report we show that the protein TTC3, encoded by one of the main DSCR candidate genes, physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two effectors of the RhoA small GTPase that have previously been involved in neuronal proliferation and differentiation. More importantly, we found that TTC3 levels can strongly affect the NGF-induced differentiation of PC12 cells, by a CIT-K-dependent mechanism. Indeed, TTC3 overexpression leads to strong inhibition of neurite extension, which can be reverted by CIT-K RNAi. Conversely, TTC3 knockdown stimulates neurite extension in the same cells. Finally, we find that Rho, but not Rho kinase, is required for TTC3 differentiation-inhibiting activity. Our results suggest that the TTC3-RhoA-CIT-K pathway could be a crucial determinant of in vivo neuronal development, whose hyperactivity may result in detrimental effects on the normal differentiation program.
Berto
Gaia
G
Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Italy.
Camera
Paola
P
Fusco
Carlo
C
Imarisio
Sara
S
Ambrogio
Chiara
C
Chiarle
Roberto
R
Silengo
Lorenzo
L
Di Cunto
Ferdinando
F
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004314:Down Syndrome / Q000235:genetics*; D004843:Epistasis, Genetic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; D020932:Nerve Growth Factor; C113619:Ttc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein