The transcription factor Meis2 promotes the development of projection neurons during mouse embryonic development by binding to and activating projection neuron-specific enhancers with Dlx5

This study investigated the role of the transcription factor Meis2 in regulating the development and differentiation of γ-aminobutyric acid (GABA)ergic neurons during mouse embryonic development. Researchers comprehensively applied techniques such as CRISPR/Cas9 knockdown, single-cell RNA sequencing (scRNA-seq), and lineage tracing, and found that Meis2 is highly expressed in the progenitor cells of projecting neurons in the embryonic basal ganglia region, which facilitates the differentiation of these progenitor cells into GABAergic projecting neurons derived from the lateral ganglionic eminence.

Meis2 cooperates with the Dlx5 family of transcription factors, binds to specific cis-regulatory elements (cREs), and activates the enhancer regions of genes related to projecting neuron differentiation, thereby inducing the fate of projecting neurons. In contrast, in the medial ganglionic eminence region, the expression of the Lhx6 transcription factor inhibits the activation of these enhancers by the Meis2-Dlx5 complex, promoting the differentiation of GABAergic interneurons.

This study used in vitro experimental systems such as reporter plasmids to verify the synergistic or antagonistic actions of Meis2 with Dlx5/Lhx6 on multiple known enhancer regions associated with GABAergic neuron development. Through the analysis of Meis2 mutants, it was found that the Arg333Lys mutation associated with intellectual disability significantly reduces the ability of Meis2 to synergistically activate with Dlx5.

In the late embryonic stage, although Meis2 mRNA is widely present in all regions of the basal ganglia, its functional activity is mainly limited to the lateral ganglionic eminence region, possibly due to the inhibition of Meis2 expression and functional activity by Lhx6 in the medial ganglionic eminence. Overall, this study revealed a new molecular mechanism determining the fate of GABAergic neurons, namely the spatially selective activation of cREs regions, a process finely regulated by the interplay of transcription factors such as Meis2, Dlx5, and Lhx6. Abnormalities in this molecular mechanism may lead to certain neurodevelopmental disorders associated with Meis2 mutations.

This research paper was published in Volume 27 of the journal Nature Neuroscience in May 2024. The first authors are Elena Dvoretskova, May C. Ho, and Volker Kittke from the Max Planck Institute for Biological Intelligence and the Max Planck Institute for Neurobiology, and the corresponding author is Christian Mayer.