Bcl11 Transcription Factors Regulate Cortical Development and Function

Abstract

Transcription factors regulate multiple processes during brain development and in the adult brain, from brain patterning to differentiation and maturation of highly specialized neurons as well as establishing and maintaining the functional neuronal connectivity. The members of the zinc-finger transcription factor family Bcl11 are mainly expressed in the hematopoietic and central nervous systems regulating the expression of numerous genes involved in a wide range of pathways. In the brain Bcl11 proteins are required to regulate progenitor cell proliferation as well as differentiation, migration, and functional integration of neural cells. Mutations of the human Bcl11 genes lead to anomalies in multiple systems including neurodevelopmental impairments like intellectual disabilities and autism spectrum disorders.

Keywords: Bcl11a; Bcl11b; brain development; hippocampus; neocortex; neural circuitry; neurological disorders; transcription factors.

FIGURE 1

Mouse Bcl11 predicted protein isoforms. (A) Alternative splicing of Bcl11a leads to four isoforms containing 1, 3, or 6 C2H2 zinc-finger domains required for DNA-binding. Exon 1 and 2 are common to all but the Bcl11a-XS isoform containing the NuRD interacting domain and a C2HC zinc-finger domain involved in protein-protein interaction. (B) Alternative splicing of Bcl11b results in three isoforms containing either all four exons or lacking exon 3 or exon 2 and 3. All Bcl11b isoforms contain the C2H2 zinc-finger domains and NuRD interacting domain. Bcl11b isoform a and b retain the C2HC zinc-finger domain which is missing in isoform c.

FIGURE 2

Bcl11 expression in the mouse brain. Bcl11 gene expression occurs early in development continuing to adulthood as shown here for the neocortex (left panels) and the hippocampus (right panels) by immuno-histochemical staining. Bcl11a (green) and Bcl11b (red) expression are shown in the neocortex at embryonic stage 14.5 (E14.5) and postnatal stage 7 (P7) and in the hippocampus at embryonic stage 18.5 (E18.5) and postnatal stage 30 (P30).