Developmental diversification of cortical inhibitory interneurons

Abstract

Summary Diverse subsets of cortical interneurons play vital roles in higher-order brain functions. To investigate how this diversity is generated, we used single cell RNA-seq to profile the transcriptomes of murine cells collected along a developmental timecourse. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental timepoints, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, revealing the embryonic emergence of interneuron cardinal subtypes. Our analysis revealed that the ASD-associated transcription factor Mef2c delineates early Pvalb-precursors, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human subtypes.

Current best practices in single‐cell RNA‐seq analysis: a tutorial

“…Many such methods involve the parametric modelling of count data. For example, Mayer et al () fit a negative binomial model to count data, using technical covariates such as the read depth and the number of counts per gene to fit the model parameters. The residuals of the model fit serve as a normalized quantification of gene expression.…”

Homochronic Transplantation of Interneuron Precursors into Early Postnatal Mouse Brains

“…It has been proposed that interneurons initially differentiate into 'cardinal classes' and then progressively mature into 'definitive classes' as they interact with their environment 11 . Recent evidence indicates that some mature interneuron subtypes may be genetically hardwired as these cells become postmitotic in the ganglionic eminences, indicating that early defined intrinsic genetic programs may play a larger role than previously appreciated 12,13 . However, the key question of how the intrinsic genetic programs interact with environmental cues to drive differentiation into distinct interneuron subtypes remains largely unexplored.…”

More than one way to induce a neuron

“…However, it might be that the induced neurons did not reach the same stage of development as endogenous cells. Matching cell types across different developmental stages remains a complex challenge in neurobiology, as shown this year by two RNA-sequencing studies 8,9 . These highlighted the difficulty of recognizing the transcription factors that define specific cell types at early stages of neuronal development in the brain's cerebral cortex.…”