Biology subjects

Foulquier, F.

Publications and source records attributed to Foulquier, F..

3 recordsLinked to original sources

bioRxiv2026

COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development

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.

cell biology↗

bioRxiv2026

Dolichol biosynthesis in yeast traces the expanded reaction pathway of higher eukaryotes

The recent reassignment of Saccharomyces cerevisiae Dfg10 as a polyprenal reductase left two unresolved steps in yeast dolichol biosynthesis: the conversion of polyprenol to polyprenal and dolichal to dolichol. In humans, both of these steps are carried out by DHRSX, an enzyme with a unique dual specificity. We found that yeast Env9 catalyzes an NADPH-dependent reduction of dolichal to dolichol. However, in contrast to DHRSX, Env9 does not catalyze the conversion of polyprenol to polyprenal. Instead, our data indicates that this reaction is catalyzed by another yeast short chain oxidoreductase, Tda5. Thus, we provide evidence that the dual role of DHRSX in human dolichol synthesis is fulfilled by two dedicated yeast enzymes, Env9 and Tda5. Accordingly, deletion of ENV9 and TDA5 led to the accumulation of polyisoprenoid intermediates, transfer of immature lipid-linked oligosaccharides onto nascent proteins, and defective N-glycosylation. This is similar to what had been observed in DHRSX-deficient mammalian cells and yeast cells with DFG10 deleted. Furthermore, we discovered that loss of Dfg10 results in a deficiency of cell wall -mannan, revealing a critical sensitivity of yeast mannan biosynthesis to the quality of nascent N-linked glycans.

biochemistry↗

bioRxiv2024

The N-glycosylation defect in Lec5 and Lec9 CHO cells is caused by absence of the DHRSX gene

Glycosylation-deficient Chinese hamster ovary (CHO) cell lines have been instrumental in the discovery of N-glycosylation machinery. Yet, the molecular causes of the glycosylation defects in the Lec5 and Lec9 mutants have been elusive, even though for both cell lines a defect in dolichol formation from polyprenol was previously established. We recently found that dolichol synthesis from polyprenol occurs in three steps consisting of the conversion of polyprenol to polyprenal by DHRSX, the reduction of polyprenal to dolichal by SRD5A3 and the reduction of dolichal to dolichol, again by DHRSX. This led us to investigate defective dolichol synthesis in Lec5 and Lec9 cells. Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency. Accordingly, N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3. Furthermore, the typical polyprenol dehydrogenase and dolichal reductase activities of DHRSX were absent in membrane preparations derived from Lec5 and Lec9 cells, while the reduction of polyprenal to dolichal, catalyzed by SRD5A3, was unaffected. Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent. Lastly, we established the sequence of Chinese hamster DHRSX and validated that this protein has similar kinetic properties to the human enzyme. Our work therefore identifies the basis of the dolichol synthesis defect in CHO Lec5 and Lec9 cells.

biochemistry↗