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Published February 2024 | Published
Journal Article Open

SMPD3 expression is spatially regulated in the developing embryo by SOXE factors


During epithelial-to-mesenchymal transition (EMT), significant rearrangements occur in plasma membrane protein and lipid content that are important for membrane function and acquisition of cell motility. To gain insight into how neural crest cells regulate their lipid content at the transcriptional level during EMT, here we identify critical enhancer sequences that regulate the expression of SMPD3, a gene responsible for sphingomyelin hydrolysis to produce ceramide and necessary for neural crest EMT. We uncovered three enhancer regions within the first intron of the SMPD3 locus that drive reporter expression in distinct spatial and temporal domains, together collectively recapitulating the expression domains of endogenous SMPD3 within the ectodermal lineages. We further dissected one enhancer that is specifically active in the migrating neural crest. By mutating putative transcriptional input sites or knocking down upstream regulators, we find that the SOXE-family transcription factors SOX9 and SOX10 regulate the expression of SMPD3 in migrating neural crest cells. Further, ChIP-seq and nascent transcription analysis reveal that SOX10 directly regulates expression of an SMPD3 enhancer specific to migratory neural crest cells. Together these results shed light on how core components of developmental gene regulatory networks interact with metabolic effector genes to control changes in membrane lipid content.

Copyright and License

© 2023 Elsevier.


We would like to thank Drs. Tatjana Sauka-Spengler, Ruth Williams, and Ivan Candido Ferreira for sharing data and helpful discussion on enhancer identification and dissection. We'd also like to thank the Caltech Biological Imaging Facility, supported by the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation, for confocal microscopy support. Funding for this work comes from the NIH grants K99/R00 DE029240 to M.L.P., R01 DE027538 to M.E.B., and a Traveling Fellowship DEVTF1908262 provided by the Company of Biologists to M.L.P.


Conceptualization: M.L.P.

Experiment design: M.L.P.

Experimentation: M.L.P., A.J.F., A.C.A., and I.G.

Data analysis: M.L.P. and A.J.F.

Data interpretation: M.L.P. and M.E.B.

Manuscript preparation: M.L.P.

Manuscript editing: M.E.B.

Data Availability

We have provided all raw source data and analysis code in our GitHub repository, linked within the manuscript.

Conflict of Interest

The authors declare no conflicts of interest.


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Additional details

December 21, 2023
January 9, 2024