Intermediate Progenitor Cohorts Differentially Generate Cortical Layers and Require Tbr2 for Timely Acquisition of Neuronal Subtype Identity.
Intermediate progenitors (IPs) amplify the production of pyramidal neurons, but their role in selective genesis of cortical layers or neuronal subtypes remains unclear. Using genetic lineage tracing in mice, we find that IPs destined to produce upper cortical layers first appear early in corticogenesis, by embryonic day 11.5. During later corticogenesis, IP laminar fates are progressively limited to upper layers. We examined the role of Tbr2, an IP-specific transcription factor, in laminar fate regulation using Tbr2 conditional mutant mice. Upon Tbr2 inactivation, fewer neurons were produced by immediate differentiation and laminar fates were shifted upward. Genesis of subventricular mitoses was, however, not reduced in the context of a Tbr2-null cortex. Instead, neuronal and laminar differentiation were disrupted and delayed. Our findings indicate that upper-layer genesis depends on IPs from many stages of corticogenesis and that Tbr2 regulates the tempo of laminar fate implementation for all cortical layers.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Anca B
AB
Mihalas
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Gina E
GE
Elsen
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Francesco
F
Bedogni
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Ray A M
RAM
Daza
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Kevyn A
KA
Ramos-Laguna
Renal Department, University Medical Centre and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology and Faculty of Medicine, University of Freiburg, 79102 Freiburg, Germany; BIOSS Centre of Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
Sebastian J
SJ
Arnold
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98104, USA. Electronic address: rhevner@uw.edu.
Robert F
RF
Hevner
D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D019070:Cell Lineage; D002540:Cerebral Cortex / Q000166:cytology*; D004622:Embryo, Mammalian / Q000166:cytology; D005786:Gene Expression Regulation; D018345:Mice, Knockout; D008938:Mitosis; D009043:Motor Activity; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D014157:Transcription Factors