Trio is a key guanine nucleotide exchange factor coordinating regulation of the migration and morphogenesis of granule cells in the developing cerebellum.
Orchestrated regulation of neuronal migration and morphogenesis is critical for neuronal development and establishment of functional circuits, but its regulatory mechanism is incompletely defined. We established and analyzed mice with neural-specific knock-out of Trio, a guanine nucleotide exchange factor with multiple guanine nucleotide exchange factor domains. Knock-out mice showed defective cerebella and severe signs of ataxia. Mutant cerebella had no granule cells in the internal granule cell layer due to aberrant granule cell migration as well as abnormal neurite growth. Trio-deficient granule cells showed reduced extension of neurites and highly branched and misguided processes with perturbed stabilization of actin and microtubules. Trio deletion caused down-regulation of the activation of Rac1, RhoA, and Cdc42, and mutant granule cells appeared to be unresponsive to neurite growth-promoting molecules such as Netrin-1 and Semaphorin 6A. These results suggest that Trio may be a key signal module for the orchestrated regulation of neuronal migration and morphogenesis during cerebellar development. Trio may serve as a signal integrator decoding extrinsic signals to Rho GTPases for cytoskeleton organization.
Peng
Ya-Jing
YJ
Model Animal Research Center and Moe Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China.
He
Wei-Qi
WQ
Tang
Jing
J
Tao
Tao
T
Chen
Chen
C
Gao
Yun-Qian
YQ
Zhang
Wen-Cheng
WC
He
Xue-Yan
XY
Dai
Yu-Yuan
YY
Zhu
Nian-Chun
NC
Lv
Ning
N
Zhang
Cheng-Hai
CH
Qiao
Yan-Ning
YN
Zhao
Li-Ping
LP
Gao
Xiang
X
Zhu
Min-Sheng
MS
D000818:Animals; D002465:Cell Movement; D002531:Cerebellum / Q000196:embryology*; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D020662:Guanine Nucleotide Exchange Factors; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010750:Phosphoproteins; C490975:Trio protein, mouse; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins