ABSTRACT
The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.
Subject(s)
Embryonic Development , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Homeodomain Proteins , Transcription Factors , Animals , Mice , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Embryonic Development/physiology , Enhancer Elements, Genetic/genetics , GABAergic Neurons/metabolism , GABAergic Neurons/physiology , Cell Differentiation/physiology , Interneurons/metabolism , Interneurons/physiology , LIM-Homeodomain Proteins/metabolism , LIM-Homeodomain Proteins/genetics , Neurogenesis/physiology , Nerve Tissue ProteinsABSTRACT
During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia1,2. The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development. We quantified clonal divergence and convergence across all major cell classes postnatally, and found diverse types of GABAergic neuron that share a common lineage. Divergence of GABAergic clones occurred during embryogenesis upon cell-cycle exit, suggesting that differentiation into subtypes is initiated as a lineage-dependent process at the progenitor cell level.
