Genetic programs and developmental trajectories of neuronal cell types

Despite their immense complexity, a unique feature of brain networks, in contrast to engineered computational networks, is that they self-assemble during the course of development. Perhaps the most complex region of the nervous system, the cerebral cortex consists of dozens of cortical areas, each comprising multiple layers and diverse neuron types, which form intricate local circuits that are integrated across global networks. A fundamental problem in neuroscience is how genome information, shaped by evolutionary processes, directs the developmental construction of a set of stereotyped and species-typic network scaffolds and circuit templates, which are then customized through individual life experiences. Unraveling the cellular and molecular basis of cortical circuit assembly has major implications in understanding and treating brain disorders from autism to intellectual disability and schizophrenia.

Our basic tenet is that, across its nested levels of organization, the cortex is fundamentally built from a large set of cardinal neuron types, which assemble 1) local connectivity according to a “canonical microcircuit template” duplicated and modified across areas, 2) species-typic intra-cortical processing streams, and 3) subcortical-directed output channels; these cardinal neuron types are reliably generated through developmental programs embedded in neural progenitors and rooted in the genome. We focus our study on two key aspects of cortical development: the lineage origin and molecular genetic basis of neuronal cell types – basic building blocks of circuit assembly. Our overarching strategy is a systematic genetic dissection of neuron types, as well as fate mapping their developmental trajectories from neural progenitors. Using driver lines and combinatorial strategies targeting progenitor subpopulations, we have discovered that fate-restricted radial glial progenitors are defined by combinatorial transcription factor (TF) expression, and lineage progression and cell birth order contribute to the cardinal identity of major glutamatergic (GLU) projection neurons (PN) and GABA interneurons (ref). For example, we are able to track the developmental trajectory of chandelier cells, a power inhibitory interneuron type that control PN spiking at the axon initial segment, from lineage origin to circuit connectivity (ref). Using a series of custom-built driver lines targeting TF-defined progenitors, we are systematically fate mapping major PN types that constitute intra-cortical processing streams (intra-telencephalic; IT) and output channels (pyramidal track; PT). These studies will provide a roadmap for tracking the assembly of cortical circuits at the resolution of cell type building blocks.

Our genetic tools enable cell type targeted transcriptomic and epigenomic analyses to discover gene expression profiles and genetic programs underlying neuron type identities. We have discovered that transcriptional signatures of synaptic input/output communication represent the essence of cortical GABAergic interneuron identity. This overarching and mechanistic definition of neuron type embodies and integrates their anatomical, physiological, and developmental genetic features. Our recent studies extend this scheme to glutamatergic pyramidal neuron types, suggesting it is likely a general defining feature for brain neuron types. We further hypothesize that cell type transcriptional signatures are orchestrated by specific gene regulatory programs that are configured in their epigenomic landscape. Through collaborations with Yarui Diao lab (epigenomics) and Jesse Gillis lab (computation analysis), we begin to test this hypothesis by applying single cell transcriptomic and epigenomic analyses to genetically targeted and fate mapped cortical GLU subpopulations using a series of mouse drive lines. We aim to reveal the genetic principles of cell type organization and provide an explanatory framework linking multi-layered molecular mechanisms to multi-faceted neuronal phenotypes for understanding brain cell diversity.

Advances in understanding the molecular and developmental basis of neuron types provide new leads to refine our genetic tools for targeting more specific cell types, as well as a broader framework for understanding circuit organization and function.  

Related Publications

Huang, ZJ, and Paul, A (2019) The diversity of GABAergic neurons and neural communication elements. Nat Rev Neurosci. 2019 Sep;20(9):563-572. doi: 10.1038/s41583-019-0195-4. PMID: 31222186 Review.

Matho, K.S., Huilgol, D., Galbavy, W., Kim, G., He, M., An, X., Lu, J., Wu, P., Di Bella, D., Shetty, A, Palaniswamy, R., Hatfield, J., Raudales, R., Narasimhan, A., Gamache, E., Levine, J., Tucciarone, J., Mitra, M., Osten, P., Arlotta, P., Huang, Z.J. Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex. Nature. 2021; 598 (7879):182-187. doi: 10.1038/s41586-021-03955-9.

Wang BS, Bernardez Sarria MS, An X, He M, Alam NM, Prusky GT, Crair MC, Huang ZJ. Retinal and Callosal Activity-Dependent Chandelier Cell Elimination Shapes Binocularity in Primary Visual Cortex. Neuron. 2021 Feb 3;109(3):502-515.e7. doi: 10.1016/j.neuron.2020.11.004.

Kelly, Sean M., Raudales, Ricardo, He, Miao, Lee, Jannifer H., Kim, Yongsoo, Gibb, Leif G., Wu, Priscilla, Matho, Katherine, Osten, Pavel, Graybiel, Ann M., Huang, Z. J. (2018) Radial Glial Lineage Progression and Differential Intermediate Progenitor Amplification Underlie Striatal Compartments and Circuit Organization. Neuron. ISSN 0896-6273

Paul A, Crow M, Raudales R, He M, Gillis J, Huang ZJ. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell. 2017 Oct 19;171(3):522-539.e20. doi: 10.1016/j.cell.2017.08.032. Epub 2017 Sep 21. PubMed PMID: 28942923; PMCID: PMC5772785.

Lu J, Tucciarone J, Padilla-Coreano N, He M, Gordon JA, Huang ZJ. Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells. Nat Neurosci. 2017 Oct;20(10):1377-1383. doi: 10.1038/nn.4624.

Taniguchi H, Lu J, Huang ZJ. The spatial and temporal origin of chandelier cells in mouse neocortex. Science. 2013 Jan 4;339(6115):70-4. PubMed PMID: 23180771; PMCID: PMC4017638.

Funding support

NIMH R01 Genetic Analysis of Chandelier Cells during Cortical Circuit Assembly

NIMH R01 Transcriptome-Based Systematic Discovery of GABAergic neurons in the neocortex

BRAIN Initiative U19; A Comprehensive Center for Mouse Brain Cell Atlas

NIMH BRAIN Initiative RF1; Discovering the molecular genetic principles of cell type organization through neurobiology-guided computational analysis of single cell multi-omics data sets.


Jesse Gillis; University of Toronto/Cold Spring Harbor Laboratory

Yarui Diao; Duke University Department of Cell Biology

Bing Ren; University of California, San Diego

Paola Arlotta, Harvard University