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Temporal Differences in Progenitor Metabolism Shape Regional Brain Growth during Development [scRNA-seq]

ABSTRACT: Temporal Differences in Progenitor Metabolism Shape Regional Brain Growth during Development [scRNA-seq]

PROVIDER: PRJNA1227531 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32473000_1.fastq.gz	Fastqsanger.gz
	SRR32473000_2.fastq.gz	Fastqsanger.gz
	SRR32473001_1.fastq.gz	Fastqsanger.gz
	SRR32473001_2.fastq.gz	Fastqsanger.gz
	SRR32473002_1.fastq.gz	Fastqsanger.gz

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Temporal Differences in Progenitor Metabolism Shape Regional Brain Growth during Development

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Project description:Mammalian brain development is characterized by disproportionate forebrain expansion, yet the mechanisms underlying this regional growth specificity remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors, maintaining its germinal pool. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late forebrain-enriched mitochondrial protein Fam210b as a key regulator using in vivo gain- and loss-of-function experiments. Fam210b elongates mitochondria and increases lactate production, which promotes progenitor self-renewing divisions and, ultimately, larger clonal size of their progeny. Together, these findings indicate spatiotemporal heterogeneity in mitochondrial function regulates progenitor cycling behavior and regional neuronal production during brain development.

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Project description:The structure of vertebrate brains emerges from a shared template where three primary regions — the hindbrain, midbrain, and forebrain — develop during embryogenesis to establish the circuits responsible for distinct functions. While the molecular mechanisms underlying the segmentation of the neural tube into these regions are relatively well understood, how their relative expansion is regulated during embryogenesis remains largely unknown. To address this question, we first generated a single-cell resolution atlas of birthdate across the entire mouse brain (https://www.neurobirth.org), which we next leveraged to identify brain-region-specific neurogenic patterns and investigate underlying molecular mechanisms. We show that in brain regions that expand, such as the neocortex, neurogenesis is sustained (sustained neurogenic regions), while it is limited to the first few days of brain development in hindbrain regions that are comparatively less developed (transient neurogenic regions). We demonstrate that sustained cortical neurogenesis is made possible by a progressive lengthening of the cell cycle and associated lower levels of consumptive divisions in apical progenitors (AP), which preserve the progenitor pool for longer periods. Finally, using single-cell RNA sequencing of AP across the developing brain, we identify spatio-temporal molecular determinants of AP cycling behavior and demonstrate a critical role for the mitochondrial membrane protein Fam210b in regulating region-specific cycling properties. These results identify a parsimonious mechanism to regulate neuronal production in different parts of the brain, in which the time window during which neurons are generated appears to be a critical determinant of a region’s expansion during development and evolution.

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