Roles of ZBTB20 in the specification of upper layer neurons and astrocytes in the neocortex

Abstract

Organization of neocortical circuits is critical for sensory perception, learning and multisensory integration. In the primary somatosensory area (S1) layer IV neurons receive thalamic inputs and synapse onto layer II/III neurons. These superficial neurons may connect other neurons within S1 and within other areas in the ipsi- or contralateral hemisphere, thus cooperating to select an interpretation consistent with their various cortical and subcortical inputs. Here we show that expression of the transcription factor Zinc Finger and BTB Domain-Containing Protein 20 (Zbtb20) in neocortical progenitors is necessary and sufficient to regulate the generation and wiring patterns of upper layer neurons. Conditional deletion of the Zbtb20 gene in progenitors leads to an increase in the number and radial occupancy of RORβ+/layer IV neurons at the expense of BRN2+/layers II/III neurons. This change in the laminar organization of the neocortex is accompanied by an expansion of thalamic axonal arborization and barrel area in S1. Furthermore, upper layer neurons increase their intra-hemispheric axonal projections, while reducing contralateral innervation in the absence of Zbtb20 expression. These alterations are also observed, albeit at a lesser extent, after Zbtb20 deletion in post-mitotic neurons, indicating that Zbtb20 act at sequential stages of the lineage progression of neocortical progenitors, fine-tuning neuronal fates in upper cortical layers and contributing to the proper wiring of callosal projecting neurons (CPNs). Besides these effects in CPN fate specification, we also show that ZBTB20 regulates astrogliogenesis in a time-specific fashion. ZBTB20 overexpression at E14, but not at E16, increases neocortical astrogliogenesis, whereas expression of a dominant-negative (DN) ZBTB20 at E16, but not E14, reduces astrogliogenesis. Altogether, our results indicate that ZBTB20 is an important regulator of cell type/subtype specification in the developing neocortex.