GABAergic neuron fate specification and lineage allocation: from development to disorder

The mammalian telencephalon contains molecularly and functionally diverse inhibitory neuron subtypes that are essential for balanced neural circuit function and dynamics. The developmental process that generates this diversity from undifferentiated neuronal progenitor cells is governed by cis-regulatory elements (CREs) and the transcription factors (TFs) that bind to them. In combination with associated transcription co-regulators and epigenetic regulators, these transcription factors form gene regulatory networks that control the establishment of lineage-specific patterns of gene expression, thereby conferring each cell type its molecular identity. Numerous genetic variants associated with neurological and mental disorders affect proteins that act at CREs or alter their regulatory activity. Mapping risk gene expression onto adult cell taxonomies, however, often fails to reveal how neuronal circuits become dysfunctional. Emerging evidence supports a model in which genetic variation modulates developmental timing, fate bias, and lineage allocation. Such modulation affects how neurons adopt particular identities and often leads to imbalanced subtype proportions among otherwise normal cell types. In this review, we synthesize findings from developmental genetics, lineage tracing, and human disease to examine how regulatory mechanisms bias inhibitory neuron fate trajectories and how genetic risk reshapes these processes during development.