Supported by:
@agencerecherche.bsky.social
@frm-officiel.bsky.social
@fondationarc.bsky.social
@cerclefser.bsky.social
@worldwidecancer.bsky.social
@institutcurie.bsky.social

This work was conducted at @institutcurie.bsky.social
in @frelab.bsky.social. Thank you for supporting my work over the last five years! Big thank also to Candice Merle, the first author of this story, for her help in the experimental work and to our collaborators at @lbmcinlyon.bsky.social.

Our work unifies decades of organ-specific studies into a single evo-devo framework. It argues for moving beyond organ-centric approaches toward cross-tissue comparisons to reveal conserved mechanisms of epithelial development, homeostasis, and disease.
www.biorxiv.org/content/10.1...

Taken together, multilayered epithelia development follows a spatial and evolutionary hourglass: basal layers reactivate an ancestral ectodermal program, while suprabasal compartments diversify through modular, lineage-specific innovations.

Lineage-tracing experiments across all 14 tissues show that activating Notch in basal cells consistently triggers suprabasal commitment, confirming the universality of this regulatory connection in stratified tissues.

Basal and suprabasal layers are linked by a conserved p63–Notch axis. p63 maintains basal identity and induces Notch ligands, whereas Notch signaling drives suprabasal commitment.

In contrast, suprabasal compartments show strong enrichment for tissue-specific and architecture-specific transcriptional modules. Functional diversification emerges primarily in suprabasal layers and follow a Russian-doll organization.

This basal program has been repeatedly redeployed (heterotopy) in endoderm- and mesoderm-derived epithelia, allowing these tissues to initiate multilayering outside their original lineage of origin.

We find that this conserved GRN is evolutionarily compartmentalized. Basal cells consistently deploy an ancestral ectodermal regulatory module centered on p63.

Comparative analyses across lamprey, zebrafish, xenopus, chicken, mouse, and human reveal that multilayered epithelia rely on a deeply conserved set of genes. This suggests that the molecular foundations of epithelial stratification were established early in vertebrate evolution.

Multilayered epithelia emerge from ectoderm, endoderm, and mesoderm, yet all adopt the same basic architecture: a basal compartment supporting one or more differentiated suprabasal layers. Do these different organs use distinct mechanisms, or a shared regulatory program?

Supported by:
@agencerecherche.bsky.social
@frm-officiel.bsky.social
@fondationarc.bsky.social
@cerclefser.bsky.social
@worldwidecancer.bsky.social
@institutcurie.bsky.social

Yes! We think this mechanism goes way beyond glands. We're now exploring a broader range of tissues, stay tuned for what's coming next!

Great question! We haven’t inferred or directly measured mechanical forces yet, but in a follow-up project we’re actively investigating the mechanical component of the symmetry-breaking event. Very curious to see how it ties into YAP localization and happy to discuss more!

This work was funded by @institutcurie.bsky.social, ‪‪‪@cnrsbiologie.bsky.social, @psl-univ.bsky.social, @agencerecherche.bsky.social , @frm-officiel.bsky.social, @cerclefser.bsky.social, @fondationarc.bsky.social and @worldwidecancer.bsky.social.

Full publication in @cp-devcell.bsky.social : authors.elsevier.com/c/1lM285Sx5g...

Despite distinct germ layer origins and divergent adult functions, all 4 glands rely on the same YAP–Notch–p63 circuit to specify fate and pattern.
We propose an updated hourglass model where this conserved module acts as a developmental bottleneck in organogenesis.