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Two parallel neural ectoderm populations contribute to the developing brain [scRNA-seq]

ABSTRACT: Stem cell research strives to create diverse types of human brain cells. Given plentiful successes in converting human pluripotent stem cells (hPSCs) into forebrain and midbrain cells, here we focus on generating cells of the human hindbrain, a life-sustaining brain region. This is, in turn, predicated on a developmental roadmap of when and how brain progenitors diversify from one another. In one model, a common brain progenitor can generate all brain regions. Here our studies of mouse embryos and hPSCs support a different model that as early as gastrulation, two parallel brain progenitors emerge simultaneously: anterior neural ectoderm (forebrain/midbrain progenitor) and posterior neural ectoderm (which forms most of the hindbrain). Expanding on classical studies, we suggest anterior and posterior neural ectoderm are already lineage-committed in vitro and cannot transdifferentiate. Anterior and posterior neural ectoderm have divergent chromatin landscapes, respectively foreshadowing their forebrain versus hindbrain potentials. We differentiated hPSCs into posterior neural ectoderm, and subsequently, hindbrain rhombomere 5/6-specific motor neurons. Anterior and posterior neural ectoderm thus represent two parallel developmental routes to generate forebrain/midbrain vs. hindbrain neurons. Finally, anterior and posterior ectoderm are likely conserved from vertebrates to hemichordates, intimating an ancient neural lineage bifurcation that predated chordates, with implications for nervous system evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286148 | GEO | 2025/01/10

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE286148_AMXC_unfiltered_hb_D4_7_processed.h5ad	Other
	GSE286148_AMXC_unfiltered_telen_D4_7_processed.h5ad	Other
	GSE286148_AMYA_unfiltered_D0-D2_processed.h5ad	Other
	GSE286148_RAW.tar	Raw

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Project description:The process that partitions the nascent vertebrate central nervous system into forebrain, midbrain, hindbrain, and spinal cord after neural induction is of fundamental interest in developmental biology, and is known to be dependent on Wnt/beta-catenin signaling at multiple steps. Neural induction specifies neural ectoderm with forebrain character that is subsequently posteriorized by graded Wnt signaling: embryological and mutant analyses have shown that progressively higher levels of Wnt signaling induce progressively more posterior fates. However, the mechanistic link between Wnt signaling and the molecular subdivision of the neural ectoderm into distinct domains in the anteroposterior (AP) axis is still not clear. To better understand how Wnt mediates neural AP patterning, we performed a temporal dissection of neural patterning in response to manipulations of Wnt signaling in zebrafish. We show that Wnt-mediated neural patterning in zebrafish can be divided into three phases: (I) a primary AP patterning phase, which occurs during gastrulation, (II) a mes/r1 (mesencephalon-rhombomere 1) specification and refinement phase, which occurs immediately after gastrulation, and (III) a midbrain-hindbrain boundary (MHB) morphogenesis phase, which occurs during segmentation stages. A major outcome of these Wnt signaling phases is the specification of the major compartment divisions of the developing brain: first the MHB, then the diencephalic-mesencephalic boundary (DMB). The specification of these lineage divisions depends upon the dynamic changes of gene transcription in response to Wnt signaling, which we show primarily involves transcriptional repression or indirect activation. We show that otx2b is directly repressed by Wnt signaling during primary AP patterning, but becomes resistant to Wnt-mediated repression during late gastrulation. Also during late gastrulation, Wnt signaling becomes both necessary and sufficient for expression of wnt8b, en2a, and her5 in mes/r1. We suggest that the change in otx2b response to Wnt regulation enables a transition to the mes/r1 phase of Wnt-mediated patterning, as it ensures that Wnts expressed in the midbrain and MHB do not suppress midbrain identity, and consequently reinforce formation of the DMB. These findings integrate important temporal elements into our spatial understanding of Wnt-mediated neural patterning and may serve as an important basis of a better understanding of neural patterning defects that have implications in human health.

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Two parallel neural ectoderm populations contribute to the developing brain [scRNA-seq]

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