TY - JOUR
T1 - An Isoform-Specific SnoN1-FOXO1 Repressor Complex Controls Neuronal Morphogenesis and Positioning in the Mammalian Brain
AU - Huynh, Mai Anh
AU - Ikeuchi, Yoshiho
AU - Netherton, Stuart
AU - de la Torre-Ubieta, Luis
AU - Kanadia, Rahul
AU - Stegmüller, Judith
AU - Cepko, Constance
AU - Bonni, Shirin
AU - Bonni, Azad
N1 - Funding Information:
We thank John Blenis and Randy King for helpful discussions, John Parnavelas for the DCX plasmids, Dan Bernard for the Smad2 RNAi plasmid, Akiyoshi Fukamizu for the Flag-FOXO1 plasmid, and members of the Bonni laboratory for helpful discussions and critical reading of the manuscript. This work was supported by NIH grants NS041021 and NS047188 (A.B.), the Canadian Institutes of Health Research and the Alberta Cancer Board (ACB) operating grants (S.B.), an ACG Postdoctoral Fellowship (S.N.), an NIH Training Grant GM077226 (M.A.H.), the Albert J. Ryan Foundation (M.A.H. and L.T.-U.), the Human Frontier Science Program Long-Term Fellowship (Y.I), the National Science Foundation (L.T.-U.), and the Deutsche Forschungsgemeinschaft (J.S.). C.C. is an investigator of the Howard Hughes Medical Institute.
PY - 2011/3/10
Y1 - 2011/3/10
N2 - Control of neuronal positioning is fundamental to normal brain development. However, the cell-intrinsic mechanisms that govern neuronal positioning remain to be elucidated. Here, we report that the spliced protein products of the transcriptional regulator SnoN, SnoN1 and SnoN2, harbor opposing functions in the coordinate regulation of neuronal branching and positioning. Knockdown of SnoN2 stimulates axon branching in primary neurons and impairs migration of granule neurons in the rat cerebellar cortex in vivo. By contrast, SnoN1 knockdown suppresses SnoN2 knockdown-induced neuronal branching and strikingly triggers excessive migration of granule neurons in the cerebellar cortex. We also find that SnoN1 forms a complex with the transcription factor FOXO1 that represses the X-linked lissencephaly gene encoding doublecortin (DCX). Accordingly, repression of DCX mediates the ability of SnoN1 to regulate branching in primary neurons and granule neuron migration in vivo. These data define an isoform-specific SnoN1-FOXO1 transcriptional complex that orchestrates neuronal branching and positioning in the brain with important implications for the study of developmental disorders of cognition and epilepsy.
AB - Control of neuronal positioning is fundamental to normal brain development. However, the cell-intrinsic mechanisms that govern neuronal positioning remain to be elucidated. Here, we report that the spliced protein products of the transcriptional regulator SnoN, SnoN1 and SnoN2, harbor opposing functions in the coordinate regulation of neuronal branching and positioning. Knockdown of SnoN2 stimulates axon branching in primary neurons and impairs migration of granule neurons in the rat cerebellar cortex in vivo. By contrast, SnoN1 knockdown suppresses SnoN2 knockdown-induced neuronal branching and strikingly triggers excessive migration of granule neurons in the cerebellar cortex. We also find that SnoN1 forms a complex with the transcription factor FOXO1 that represses the X-linked lissencephaly gene encoding doublecortin (DCX). Accordingly, repression of DCX mediates the ability of SnoN1 to regulate branching in primary neurons and granule neuron migration in vivo. These data define an isoform-specific SnoN1-FOXO1 transcriptional complex that orchestrates neuronal branching and positioning in the brain with important implications for the study of developmental disorders of cognition and epilepsy.
UR - http://www.scopus.com/inward/record.url?scp=79952230615&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.02.008
DO - 10.1016/j.neuron.2011.02.008
M3 - Article
C2 - 21382553
AN - SCOPUS:79952230615
SN - 0896-6273
VL - 69
SP - 930
EP - 944
JO - Neuron
JF - Neuron
IS - 5
ER -