The Embryonic Specification of Interneurons
How do interneurons acquire their emergent properties? Are their morphologies, physiological properties and connectivity intrinsically programmed or imposed through extracellular cues as they develop? The Fishell Laboratory is interested in determining the genetic and developmental origins of inhibitory interneuron diversity. Virtually all cortical interneurons arise from two transient developmental structures, the Medial and Caudal Ganglionic Eminences (MGE and CGE, respectively). Our working hypothesis is that upon becoming postmitotic, the activation of gene regulatory networks establishes an array of interneuron classes. Understanding the specifics of the intrinsic programs that create these classes represents one of our fundamental focuses. Using genetics and epigenetics to study the emergence of interneuron classes, we are complementing single cell transcriptomics with the use of complementary approaches to probe the chromatin landscape (Allaway et al., Nature 2021, Bandler et al., Nature 2022). Together, these are providing us with insights as to the developmental genetic programs underlying interneuron subtype specification. While interneuron identity may be initially imposed upon becoming postmitotic, their subtype character progressively emerges as the cells reach their settling position within the cortex. The challenge is to understand when and how their mature properties are acquired. This appears to be dictated by a remarkable interplay of intrinsic gene regulatory programs modified by developmentally-timed extrinsic signals. Through the use of a combination of new methods such as single cell RNA-seq, ATAC-seq, CUT&RUN, complemented by spatio-transcriptomics (Slide-seq, MERFISH), the ability to probe both intrinsic and extrinsic signals longitudinally across development is rapidly advancing.
Newly born GABAergic sister cells diverge into different precursor states
UMAP representation of interneuron (Branch 1) emergence
PV and SST interneurons resolve into distinct gene regulatory networks over development
Selected References
Mayer C, Fishell G. Developing neurons are innately inclined to learn on the job. Nature. 2018 Jul 23; doi 10.1038/d41586-018-05737-2.
Allaway KC, Gabitto MI, Wapinski O, Saldi G, Wang C-Y, Bandler RC, Wu SJ, Bonneau R, Fishell G. Genetic and epigenetic coordination of cortical interneuron development. Nature. 2021 Sep;597(7878):693–697. PMID: 3455224
Bandler RC, Vitali I, Delgado RN, Ho MC, Dvoretskova E, Ibarra Molinas JS, Frazel PW, Mohammadkhani M, Machold R, Maedler S, Liddelow SA, Nowakowski TJ, Fishell G, Mayer C. Single-cell delineation of lineage and genetic identity in the mouse brain. Nature. 2022 Jan;601(7893):404–409. PMCID: PMC8770128
Fishell G, Kepecs A. Interneuron Types as Attractors and Controllers. Annu Rev Neurosci. 2020 Jul 8;43:1-30. doi: 10.1146/annurev-neuro-070918-050421. Epub 2019 Jul 12.PMID: 31299170