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. [Display omitted] •Intermediate progenitors (IPs) generate all types of cortical projection neurons•A subset of early IPs produces upper-layer neurons•Projection neuron laminar fates are dysregulated in the Tbr2-deficient cortex•Tbr2 is mainly necessary for differentiation, not genesis, of IPs The role of intermediate progenitors (IPs) in corticogenesis has been unclear. Mihalas et al. show that early IP cohorts produce lower- and upper-layer neurons and that Tbr2 is required to regulate differentiation, not genesis, of IPs.