Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

Abstract

The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show that Prdm16 expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

Transcriptional profiling of sequentially generated septal neuron fates

“…We noticed that Prdm16 is highly expressed in both RG and newborn neurons, especially late-born (Figure 2E,H). In other parts of the developing brain, Prdm16 is expressed exclusively in radial glia, and quickly shut down as cells become intermediate progenitors (Baizabal et al, 2018;Turrero Garcia et al, 2020). Its upregulation to even higher levels in septal neurons could reflect a novel role for this gene in the control of further aspects of neuronal differentiation, especially in the LS.…”

A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli

“…Deletion of Prdm16 in Nkx2.1-expressing progenitors leads to the loss of approximately 30% of cortical interneurons derived from the MGE/PoA, whose function is partially compensated by other developmental lineages 15 . By contrast, septal eminence-derived Nkx2.1-lineage neurons in the LS appear to be especially susceptible to the loss of Prdm16, since it results in their almost complete ablation (Figures 1, S1).…”

“…In the MGE/PoA, expression of Prdm16 is confined to progenitors, where it controls their proliferative capacity 15 . In the developing septum, Prdm16 expression is sustained in postmitotic neurons 10,41 , potentially reflecting a specific need for this gene in the survival of septal neurons.…”

“…This could be due to the increased variability in the exploratory behavior of individual male mice, which might obscure our MoSeq analyses in this specific context 47 . Another important consideration is the loss of other forebrain Nkx2.1-lineage neurons, including about 30% of cortical interneurons, in cKO mice 15 .…”

“…In a recent study, we generated a mouse line where Prdm16, a gene encoding a transcriptional regulator, was deleted from cells with a developmental history of expression of Nkx2.1. This led to a decrease in the number of interneurons derived from the medial ganglionic eminence (MGE) in the cerebral cortex and other brain areas such as the hippocampus and the nucleus accumbens 15 . Here we report an almost complete ablation of Nkx2.1-lineage neurons in the lateral, but not the medial, septum.…”