by Miguel Turrero García and Corey Harwell

The cerebral cortex is home to an extraordinarily diverse population of cells, which act in concert to form and maintain the circuits that are responsible for how animals respond to and interact with their environment. Neurons can be classified into two main categories: most of them (about 80% in the mouse cortex) are excitatory neurons, while the rest are inhibitory interneurons, which are responsible for modulating circuit activity. Each of these groups is born from neural progenitors located in a different part of the developing brain – pyramidal neurons are born in what will become the cortex, while most interneurons originate in a structure located in the ventral portion of the embryonic forebrain, called the medial ganglionic eminence (MGE).

A pair of newborn cortical interneuron
progenitors in the brain of a mouse embryo

The production and maintenance of the right number of interneurons is important to maintain the excitatory/inhibitory balance, which is disrupted in conditions such as epilepsy, autism or bipolar disorder. Previous work in our lab showed that that the transcriptional regulator PRDM16 controls the correct progression of neurogenesis and ensures the production of proper numbers of upper-layer pyramidal neurons and their radial migration into the developing cortex (see Baizabal et al. 2018).

We decided to test its role in the production of interneurons by generating mutant mice where the Prdm16 gene was specifically deleted in MGE progenitors. These mice lost about 30% of cortical interneurons that come from these progenitors, disrupting the excitatory/inhibitory balance. Loss of Prdm16 caused defects in the proliferative capacity of the neural progenitor cells, rather than failures in migration or misspecification of interneurons that would lead to cell death. We discovered that PRDM16 regulates the expression of sets of genes that are unique to either cortical or MGE progenitors, suggesting that it might act in concert with local signals in either proliferative region.

Our findings, produced in collaboration with colleagues within the department and at Dana-Farber, were recently published (Turrero García et al., 2020). We hope that our study will not only contribute to our understanding of cortical interneuron generation and the mechanisms by which PRDM16 exerts its functions in the context of brain development, but also will help to highlight the importance of biological context when studying the role of transcriptional regulators.

Miguel Turrero García is a postdoctoral fellow in the lab of Corey Harwell, in the Department of Neurobiology at Harvard Medical School.

This work was funded by HBI Bipolar Disorder Seed Grants made possible by the Dauten Family Foundation, as well as the Ellen R. and Melvin J. Gordon Center for the Cure and Treatment of Paralysis and the National Institutes of Health (R01MH119156 and R01NS102228).

This story will also be featured in the HMS Neurobiology Department newsletter, The Action Potential.

Learn more in the original research article:
Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production. Turrero García M, Baizabal JM, Tran DN, Peixoto R, Wang W, Xie Y, Adam MA, English LA, Reid CM, Brito SI, Booker MA, Tolstorukov MY, Harwell CC.Development. 2020 Nov 16;147(22):dev187526. doi: 10.1242/dev.187526. 

You can also view a Twitter digest of this work here:
https://twitter.com/miguel_turrero/status/1318630721070764033
Miguel’s twitter handle is @miguel_turrero and the Harwell Lab’s is @harwell_lab.