Stem cell reportsSep 24, 2026

HOPX controls the growth and development path of human stem cell–derived outer radial glia–like cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 25, 2026

Abstract

HOPX loss results in impaired expansion and lineage progression of outer radial glia-like cells.

Knockout of HOPX in human pluripotent stem cells leads to reduced cell proliferation and neurogenesis.
HOPX-deficient cells show premature differentiation towards astrocytes and oligodendrocytes.
Cortical organoids lacking HOPX exhibit a smaller outer subventricular zone and decreased neuronal output.
Loss of HOPX disrupts PI3K-mTOR signaling pathways.
Transcriptomic analysis reveals HOPX-regulated pathways related to gliogenic competence, mTOR, and Wnt signaling.

Simplified

Outer radial glia (oRG) are abundant in the human fetal cortex but rare in rodents, yet their molecular regulation remains poorly understood. Although the homeodomain-only protein X (HOPX) is a well-established oRG marker, its functional role in human cortical development remains undefined. Using CRISPR-Cas9 gene editing in human pluripotent stem cells, we show that HOPX loss impairs the expansion and lineage progression of oRG-like cells in two-dimensional neural cultures and three-dimensional cortical organoids. HOPX knockout precursors exhibit reduced proliferation, diminished neurogenesis, and premature differentiation toward astrocytic and oligodendrocytic lineages. HOPX-deficient organoids display reduced outer subventricular zone size, decreased neuronal output, and early gliogenesis. Mechanistically, HOPX loss impairs PI3K-mTOR signaling. Transcriptomic analysis identifies HOPX-regulated programs governing gliogenic competence, mTOR, and Wnt signaling. Together, these findings identify HOPX as an important regulator of oRG-like cell maintenance and the neurogenic-gliogenic balance, providing insight into the molecular programs governing human neural progenitor expansion.

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HOPX controls the growth and development path of human stem cell–derived outer radial glia–like cells

Abstract

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