The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

Simple Summary Neurodevelopmental disorders are typically attributed to abnormal brain development. These disorders encompass a wide range of neuropsychiatric symptoms that can result in varying degrees of mental, physical, and economic consequences for the affected individuals, their families, and society. Most treatments available today are symptomatic. To develop more curative therapeutic approaches, it is necessary to identify the precise cellular and molecular mechanisms underlying neurodevelopmental disorders. Recently, mutations in BCL11A and BCL11B, two ultra-conserved zinc-finger transcription factors, have been associated with multiple cases of neurodevelopmental disorders, including developmental delay, autism spectrum disorder, intellectual disability, and structural brain alterations. Model organisms revealed Bcl11 transcription factors to be critical regulators of nervous system development. They are involved in neural progenitor cell proliferation, migration, differentiation, and synapse formation. Targeted mutations of Bcl11a and Bcl11b in mice result in phenotypic features remarkably similar to the corresponding disorders observed in humans. This makes animal models valuable tools for a better understanding of pathogenic mechanisms. This review provides a comprehensive overview of our current understanding of the functions of Bcl11 transcription factors in brain development. It links fundamental experimental research with the emerging amount of clinical and genetic data from individuals affected by Bcl11a- and Bcl11b-dependent neurodevelopmental disorders. Abstract Neurodevelopmental disorders (NDDs) comprise a diverse group of diseases, including developmental delay, autism spectrum disorder (ASD), intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD). NDDs are caused by aberrant brain development due to genetic and environmental factors. To establish specific and curative therapeutic approaches, it is indispensable to gain precise mechanistic insight into the cellular and molecular pathogenesis of NDDs. Mutations of BCL11A and BCL11B, two closely related, ultra-conserved zinc-finger transcription factors, were recently reported to be associated with NDDs, including developmental delay, ASD, and ID, as well as morphogenic defects such as cerebellar hypoplasia. In mice, Bcl11 transcription factors are well known to orchestrate various cellular processes during brain development, for example, neural progenitor cell proliferation, neuronal migration, and the differentiation as well as integration of neurons into functional circuits. Developmental defects observed in both, mice and humans display striking similarities, suggesting Bcl11 knockout mice provide excellent models for analyzing human disease. This review offers a comprehensive overview of the cellular and molecular functions of Bcl11a and b and links experimental research to the corresponding NDDs observed in humans. Moreover, it outlines trajectories for future translational research that may help to better understand the molecular basis of Bcl11-dependent NDDs as well as to conceive disease-specific therapeutic approaches.