Developmental single-cell transcriptomics of hypothalamic POMC neurons reveal the genetic trajectories of multiple neuropeptidergic phenotypes

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Abstract

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential to regulate food intake and energy balance. However, the ontogenetic transcriptional programs that specify the identity and functioning of these neurons are poorly understood. Here, we use scRNAseq to define the transcriptomes characterizing Pomc-expressing cells in the developing hypothalamus and TRAP-seq to analyze the subsequent translatomes of mature POMC neurons. Our data showed that Pomc-expressing neurons give rise to multiple developmental pathways expressing different levels of Pomc and unique combinations of transcription factors. The predominant cluster, featured by high levels of Pomc and Prdm12 transcripts represents the canonical arcuate POMC neurons. Additional cell clusters expressing medium or low levels of Pomc mature into different neuronal phenotypes featured by distinct sets of transcription factors, neuropeptides, processing enzymes, cell surface and nuclear receptors. We conclude that the genetic programs specifying the identity and differentiation of arcuate POMC neurons are diverse and generate a heterogeneous repertoire of neuronal phenotypes early in development that continue to mature postnatally.

Data availability

All raw data have been deposited in the Gene Expression Omnibus under accession numbers GSE154153 and GSE181539.

The following data sets were generated

(2021) Single cell RNA-seq of the developing mouse hypothalamus
NCBI Gene Expression Omnibus, GSE154153.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154153
(2021) Developmental single-cell transcriptomics of hypothalamic POMC progenitors reveal the genetic trajectories of multiple neuropeptidergic phenotypes
NCBI Gene Expression Omnibus, GSE181539.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE181539

Article and author information

Author details

Hui Yu

Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States

For correspondence
huiyuz@umich.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5249-0193
Marcelo Rubinstein

Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States

For correspondence
mrubins@dna.uba.ar

Competing interests
The authors declare that no competing interests exist.
Malcolm J Low

Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States

For correspondence
mjlow@umich.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9900-3708

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK068400)

Malcolm J Low

National Institute of Diabetes and Digestive and Kidney Diseases (DK068400)

Marcelo Rubinstein

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were performed in accordance with the Institutional Animal Care and Use Committee (IACUC) protocol (PRO00008570) at the University of Michigan and followed the Public Health Service guidelines for the humane care and use of experimental animals.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.