TY - JOUR
T1 - SMAD4 is essential for generating subtypes of neurons during cerebellar development
AU - Fernandes, Marie
AU - Antoine, Michelle
AU - Hébert, Jean M.
N1 - Funding Information:
We are grateful to Nicholas McKeehan for technical assistance, Celine Zimmer for help with the DIG RNA in situ hybridization protocol, to Chuxia Deng and Alex Joyner for mice and to Jane Johnson for the Atoh1 plasmid; to our laboratory members, to Zaven Kaprielian, Stacey Reeber and Roy Sillitoe for insightful discussions and comments on the manuscript. This work was supported by grants MH083804 and MH070596 from NIH and from the McDonnell Brain Tumor Foundation (JMH).
PY - 2012/5/1
Y1 - 2012/5/1
N2 - Cerebellum development involves the coordinated production of multiple neuronal cell types. The cerebellar primordium contains two germinative zones, the rhombic lip (RL) and the ventricular zone (VZ), which generate different types of glutamatergic and GABAergic neurons, respectively. What regulates the specification and production of glutamatergic and GABAergic neurons as well as the subtypes for each of these two broad classes remains largely unknown. Here we demonstrate with conditional genetic approaches in mice that SMAD4, a major mediator of BMP and TGFβ signaling, is required early in cerebellar development for maintaining the RL and generating subsets of RL-derived glutamatergic neurons, namely neurons of the deep cerebellar nuclei, unipolar brush cells, and the late cohort of granule cell precursors (GCPs). The early cohort of GCPs, despite being deficient for SMAD4, is still generated. In addition, the numbers of GABAergic neurons are reduced in the mutant and the distribution of Purkinje cells becomes abnormal. These studies demonstrate a temporally and spatially restricted requirement for SMAD4 in generating subtypes of cerebellar neurons.
AB - Cerebellum development involves the coordinated production of multiple neuronal cell types. The cerebellar primordium contains two germinative zones, the rhombic lip (RL) and the ventricular zone (VZ), which generate different types of glutamatergic and GABAergic neurons, respectively. What regulates the specification and production of glutamatergic and GABAergic neurons as well as the subtypes for each of these two broad classes remains largely unknown. Here we demonstrate with conditional genetic approaches in mice that SMAD4, a major mediator of BMP and TGFβ signaling, is required early in cerebellar development for maintaining the RL and generating subsets of RL-derived glutamatergic neurons, namely neurons of the deep cerebellar nuclei, unipolar brush cells, and the late cohort of granule cell precursors (GCPs). The early cohort of GCPs, despite being deficient for SMAD4, is still generated. In addition, the numbers of GABAergic neurons are reduced in the mutant and the distribution of Purkinje cells becomes abnormal. These studies demonstrate a temporally and spatially restricted requirement for SMAD4 in generating subtypes of cerebellar neurons.
KW - Deep cerebellar nuclei
KW - Granule cell precursor
KW - Mouse
KW - Rhombic lip
KW - SMAD4
KW - Unipolar brush cells
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U2 - 10.1016/j.ydbio.2012.02.017
DO - 10.1016/j.ydbio.2012.02.017
M3 - Article
C2 - 22370000
AN - SCOPUS:84859431030
SN - 0012-1606
VL - 365
SP - 82
EP - 90
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -