Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages

Dev Cell. 2022 Sep 26;57(18):2181-2203.e9. doi: 10.1016/j.devcel.2022.08.009. Epub 2022 Sep 14.


Many developmental signaling pathways have been implicated in lineage-specific differentiation; however, mechanisms that explicitly control differentiation timing remain poorly defined in mammals. We report that murine Hedgehog signaling is a heterochronic pathway that determines the timing of progenitor differentiation. Hedgehog activity was necessary to prevent premature differentiation of second heart field (SHF) cardiac progenitors in mouse embryos, and the Hedgehog transcription factor GLI1 was sufficient to delay differentiation of cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro, akin to that of SHF progenitors in vivo, which prevented the onset of the cardiac differentiation program. A Hedgehog signaling-dependent active-to-repressive GLI transition functioned as a differentiation timer, restricting the progenitor network to the SHF. GLI1 expression was associated with progenitor status across germ layers, and it delayed the differentiation of neural progenitors in vitro, suggesting a broad role for Hedgehog signaling as a heterochronic pathway.

Keywords: GLI transcription factors; Hedgehog signaling; congenital heart disease; differentiation; epigenetics; gene regulatory network; heart development; heterochrony; neuronal development; progenitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Gene Regulatory Networks*
  • Hedgehog Proteins* / genetics
  • Hedgehog Proteins* / metabolism
  • Mice
  • Signal Transduction / physiology
  • Zinc Finger Protein GLI1 / genetics


  • Hedgehog Proteins
  • Zinc Finger Protein GLI1