Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm

Abstract

Despite long-standing epidemiological associations, the mechanism linking folate availability to gestational neural tube defects remains unclear, partly because measuring and interpreting metabolic activity in dynamic biological systems remains challenging. Here, we apply a deep-learning-based graph-guided variational autoencoder (MeRN; Metabolic Representation Network) to infer single-cell metabolic activity and states from scRNA-seq data of mouse embryogenesis. By analyzing folate-deficient embryogenesis from E7.0 to E9.0, we identify a transient state within the nascent neural lineage that is acutely sensitive to folate availability, leading to an interconnected disruption between key bioenergetic pathways and de novo purine biosynthesis. Moreover, metabolically induced growth defects lead to permanent morphological disruptions along the dorsal-ventral axis, which we confirm by generating whole-embryo fate maps using a prime-editing-based lineage recorder (PEtracer). Collectively, our results establish a highly scalable framework for interpreting dynamic changes in embryonic metabolism and elucidating the mechanistic bases underlying environmentally linked congenital disorders.

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BibTeX RIS

BibTeX

@misc{dias2026folate,
  title = {{Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm}},
  author = {N. Dias and D. P. Lewinsohn and W. N. Colgan and M. Wang and Y. Kijima and J. Villagrana and T.-C. J. Hou and G. Gowri and A. Chau and T. Aktas and K. Sumigray and J. S. Weissman and L. W. Koblan and A. Wagner and Z. D. Smith},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.18.752622},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752622v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm
AU  - N. Dias
AU  - D. P. Lewinsohn
AU  - W. N. Colgan
AU  - M. Wang
AU  - Y. Kijima
AU  - J. Villagrana
AU  - T.-C. J. Hou
AU  - G. Gowri
AU  - A. Chau
AU  - T. Aktas
AU  - K. Sumigray
AU  - J. S. Weissman
AU  - L. W. Koblan
AU  - A. Wagner
AU  - Z. D. Smith
PY  - 2026
DA  - 2026/09/18
PB  - bioRxiv
DO  - 10.64898/2026.09.18.752622
UR  - https://www.biorxiv.org/content/10.64898/2026.09.18.752622v1
AB  - Despite long-standing epidemiological associations, the mechanism linking folate availability to gestational neural tube defects remains unclear, partly because measuring and interpreting metabolic activity in dynamic biological systems remains challenging. Here, we apply a deep-learning-based graph-guided variational autoencoder (MeRN; Metabolic Representation Network) to infer single-cell metabolic activity and states from scRNA-seq data of mouse embryogenesis. By analyzing folate-deficient embryogenesis from E7.0 to E9.0, we identify a transient state within the nascent neural lineage that is acutely sensitive to folate availability, leading to an interconnected disruption between key bioenergetic pathways and de novo purine biosynthesis. Moreover, metabolically induced growth defects lead to permanent morphological disruptions along the dorsal-ventral axis, which we confirm by generating whole-embryo fate maps using a prime-editing-based lineage recorder (PEtracer). Collectively, our results establish a highly scalable framework for interpreting dynamic changes in embryonic metabolism and elucidating the mechanistic bases underlying environmentally linked congenital disorders.
ER  -

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