Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway I

Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper-layer cortical projection neurons during postnatal corticogenesis. We used this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we found Bcl6, previously shown to be involved in transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major check point regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6-dependent molecular pathway in regulation of developmental cell death during corticogenesis. Neocortical layers II-IV were laser-microdissected from four control (Bcl11a flox/+;Emx1 IRESCre/+) and four Bcl11a mutant (Bcl11a flox/flox;Emx1 IRESCre/+) pups at P2. Total RNA was isolated using the RNeasy Micro Plus Kit (Qiagen). The isolated RNA was checked for purity and integrity using Nanodrop spectrophotometer and TapeStation (Agilent), respectively. Transcriptome analysis was performed using GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix) and BRB-ArrayTools developed by Dr. Richard Simon and BRB-ArrayTools Development Team (http://linus.nci.nih.gov/BRB-ArrayTools.html).