Interneuron Developmental Diversification

 

Nature volume 555, pages 457–462 (22 March 2018)

Developmental diversification of cortical inhibitory interneurons

Christian Mayer, et.al.

NYU Neuroscience Institute, Langone Medical Center, New York, New York 10016, USA

New York Genome Center, New York, New York 10013, USA.

Harvard Medical School, Department of Neurobiology, Boston, Massachusetts 02115, USA

Broad Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts 02142, USA

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA

Center for Genomics and Systems Biology, New York University, New York, New York 10012, USA

Center for Genomics and Systems Biology, New York University, PO Box 129188, Saadiyat Island, Abu Dhabi, United Arab Emirates

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Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single-cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. 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 time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, 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 interneuron subtypes.

Cortical inhibitory neurons are a diverse population that varies widely in morphology, connectivity and patterns of activity. This group of neurons is developmentally derived from progenitors located in embryonic proliferative zones known as the medial, caudal and lateral ganglionic eminences (MGE, CGE and LGE, respectively). Although each eminence gives rise to non-overlapping types of interneurons, the genetic programs driving interneuron fate specification and maintenance are not well understood. Diversity is first apparent in the regional expression of a limited number of transcription factors within the ganglionic eminences. For example, the transcription factor Nkx2-1 is expressed throughout the entire MGE, but is not expressed in the CGE or LGE4, whereas the transcription factor Lhx8 is expressed only within a subdomain of the MGE2. However, how these early sources of heterogeneity generate the vast diversity of adult interneurons remains unclear, a question that is complicated by the fact that the ganglionic eminences also generate numerous subcortical projection neuron types such as the cholinergic cells of the basal ganglia.

Here we combine multiple single-cell RNA sequencing (scRNA-seq) approaches with genetic fate-mapping techniques to explore the emergence of cellular heterogeneity during early mouse development. Within mitotic progenitors, we found a highly conserved maturation trajectory, accompanied by eminence-specific transcription factor expression that seeds the emergence of later cell diversity. Alongside the exit from the cell cycle, we reconstructed bifurcations into three distinct precursor states, which were highly correlated across eminences, and included a cortical interneuron ground state. Lastly, guided by the genetic diversity seen in mature populations, we connected the transcriptomic heterogeneity of adult interneurons with their embryonic precursors. Our integrated longitudinal analysis reveals the emergence of interneuron subtype identity during development, and identifies genetic regulators responsible for these fate decisions.

Our work reveals how subtype-specific heterogeneity progresses from the expression of cardinal genes in progenitors to the emergence of specific subtypes that populate the mature cortex. Postmitotic cells in the ganglionic eminences branch into distinct precursor states, representing populations fated to give rise to interneurons or projection neurons. It seems probable that the superimposition of precursor-state genes and eminence-specific genes act coordinately to bestow the common and unique characteristics within particular GABAergic populations, respectively.

Consequently, precursor genes are likely to direct the developmental cascade and acquisition of general properties that are shared within a given type. This probably ensures, for instance, that interneurons migrate tangentially to the cortex or the hippocampus, whereas projection neurons remain positioned ventrally and form long-range projections. Supplementing these more general programs are the eminence-specific genes that, for example, may direct the axons of parvalbumin cortical interneurons to form perisomal baskets and the efferents of somatostatin cortical interneurons to reliably target dendrites. These distinct differentiation modules reflect the major cardinal types of cortical interneuron precursors.

The identification of early precursors offers insight into how specific cell types emerge and provides genetic access to immature cortical interneuron subtypes. To broaden the implications of these results, our findings indicate that components of the transcriptional networks underlying interneuron fate specification are conserved between mouse and human, including Mef2c and other genes associated with neuropsychiatric disorders. This highlights the power of combining single-cell genomics with analytical tools to identify genes that have important functional roles in the establishment and maintenance of interneuron fates. Our findings mark an initial but important step towards the goal of ultimately linking specific genes to their aetiology in neurodevelopmental and neuropsychiatric disorders.

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