COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development
- 1Human Technopole, Viale Rita Levi Montalcini, Milan, IT
Abstract
Apical radial glial cells (aRGs) are highly polarized epithelial cells that drive human cortical development through tightly regulated lineage progression. A distinctive feature of aRGs is their non-canonical Golgi organization, raising the possibility that specialized intracellular trafficking and secretory processes contribute to progenitor behaviour. However, how Golgi architecture contributes to human corticogenesis remains poorly understood. Here, we investigate this question in the context of COG5 deficiency, a rare congenital disorder of glycosylation associated with neurodevelopmental defects, using patient-derived fibroblasts and brain organoids, N-glycomics, glycolipidomics, and single-cell transcriptomics. We show that COG5 deficiency disrupts Golgi organization and impairs Golgi-to-ER retrograde trafficking. At the neurodevelopmental level, COG5-deficient organoids display altered ventricular organization and reduced basal progenitor abundance. Single-cell transcriptomic analysis reveals rewired developmental trajectories characterized by premature differentiation from apical progenitors with activation of neuronal pathways. Despite the absence of major abnormalities in plasma glycoproteins glycosylation, glycolipidomic analysis identified marked defects in glycosphingolipid maturation within patient-derived brain organoids, indicating selective impairment of neural lipid glycosylation. Transcriptomic and biochemical analyses further revealed dysregulation of developmental pathways, including reduced Notch signalling and altered localization of both cleaved Notch1 and the Golgi-associated protein ACBD3. Consistent with impaired progenitor maintenance, COG5-deficient organoids displayed altered cleavage plane orientation in apical progenitors. Together, our findings suggest a link between Golgi organization, intracellular trafficking, membrane glycosylation, and lineage progression in human neural progenitors, identifying Golgi architecture as an important regulator of apical radial glial cell biology and cortical development.
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BibTeX
@misc{polenghi2026cog5mediated,
title = {{COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development}},
author = {M. Polenghi and E. Restelli and A. Janez Pedrayes and B. Ghesquiere and M. Galimberti and V. Rava and G. Visani and S. Amin and C. Cheroni and R. Bosotti and S. Terzoli and I. Taleb Arrada and O. Prodhomme and F. Alkar and M. Mezaros and S. Vuillaumier Barrot and A. Bruneel and P. Witters and M. Willems and F. Foulquier and E. Taverna},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.760061},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.760061v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development
AU - M. Polenghi
AU - E. Restelli
AU - A. Janez Pedrayes
AU - B. Ghesquiere
AU - M. Galimberti
AU - V. Rava
AU - G. Visani
AU - S. Amin
AU - C. Cheroni
AU - R. Bosotti
AU - S. Terzoli
AU - I. Taleb Arrada
AU - O. Prodhomme
AU - F. Alkar
AU - M. Mezaros
AU - S. Vuillaumier Barrot
AU - A. Bruneel
AU - P. Witters
AU - M. Willems
AU - F. Foulquier
AU - E. Taverna
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.760061
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.760061v1
AB - Apical radial glial cells (aRGs) are highly polarized epithelial cells that drive human cortical development through tightly regulated lineage progression. A distinctive feature of aRGs is their non-canonical Golgi organization, raising the possibility that specialized intracellular trafficking and secretory processes contribute to progenitor behaviour. However, how Golgi architecture contributes to human corticogenesis remains poorly understood. Here, we investigate this question in the context of COG5 deficiency, a rare congenital disorder of glycosylation associated with neurodevelopmental defects, using patient-derived fibroblasts and brain organoids, N-glycomics, glycolipidomics, and single-cell transcriptomics. We show that COG5 deficiency disrupts Golgi organization and impairs Golgi-to-ER retrograde trafficking. At the neurodevelopmental level, COG5-deficient organoids display altered ventricular organization and reduced basal progenitor abundance. Single-cell transcriptomic analysis reveals rewired developmental trajectories characterized by premature differentiation from apical progenitors with activation of neuronal pathways. Despite the absence of major abnormalities in plasma glycoproteins glycosylation, glycolipidomic analysis identified marked defects in glycosphingolipid maturation within patient-derived brain organoids, indicating selective impairment of neural lipid glycosylation. Transcriptomic and biochemical analyses further revealed dysregulation of developmental pathways, including reduced Notch signalling and altered localization of both cleaved Notch1 and the Golgi-associated protein ACBD3. Consistent with impaired progenitor maintenance, COG5-deficient organoids displayed altered cleavage plane orientation in apical progenitors. Together, our findings suggest a link between Golgi organization, intracellular trafficking, membrane glycosylation, and lineage progression in human neural progenitors, identifying Golgi architecture as an important regulator of apical radial glial cell biology and cortical development.
ER -