The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.
The T-box containing Tbr2 gene encodes for a transcription factor essential for the specification of the intermediate neural progenitors (INPs) originating the excitatory neurons of the cerebral cortex. However, its overall mechanism of action, direct target genes and cofactors remain unknown. Herein, we carried out global gene expression profiling combined with genome-wide binding site identification to determine the molecular pathways regulated by TBR2 in INPs. This analysis led to the identification of novel protein-protein interactions that control multiple features of INPs including cell-type identity, morphology, proliferation and migration dynamics. In particular, NEUROG2 and JMJD3 were found to associate with TBR2 revealing unexplored TBR2-dependent mechanisms. These interactions can explain, at least in part, the role of this transcription factor in the implementation of the molecular program controlling developmental milestones during corticogenesis. These data identify TBR2 as a major determinant of the INP-specific traits by regulating both genetic and epigenetic pathways.
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute , 20132 Milan, Italy.
Alessandro
A
Sessa
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute , 20132 Milan, Italy.
Ernesto
E
Ciabatti
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway ,LondonNW7 1AA, UK.
Daniela
D
Drechsel
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute , 20132 Milan, Italy.
Luca
L
Massimino
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute , 20132 Milan, Italy.
Gaia
G
Colasante
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute , 20132 Milan, Italy.
Serena
S
Giannelli
Laboratory of Host Defense, Osaka University, Osaka565-0871, Japan.
Takashi
T
Satoh
Laboratory of Host Defense, Osaka University, Osaka565-0871, Japan.
Shizuo
S
Akira
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway ,LondonNW7 1AA, UK.
Francois
F
Guillemot
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.|CNR Institute of Neuroscience, 20129 Milan, Italy.
Vania
V
Broccoli
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics* / Q000502:physiology; D053263:Gene Regulatory Networks / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C491198:Eomes protein, mouse; C102938:Neurog2 protein, mouse; C523761:Kdm6b protein, mouse
Tbr2; intermediate neural progenitors; neurog2; neurogenesis