Shifts in embryonic oxygen levels cue heterochrony in limb initiation.

Heterochrony, or the alteration of developmental timing, is an important mechanism of evolutionary change. Avian species display synchronized growth of the forelimbs and hindlimbs, while mammalian species show delayed hindlimb development. We find that mammalian limb heterochrony is evident from the start of limb bud formation and is associated with heterochronic expression of T-box transcription factors. This heterochronic shift is not due to changes in cis-regulatory sequences controlling T-box gene expression but, unexpectedly, is dependent upon the differential oxygen levels to which avian and mammalian embryos are exposed prior to limb initiation. This is mediated, at least partially, by cRel, a transcription factor in the nuclear factor κB (NF-κB) family, and by the oxygen-sensing transcription factor hypoxia-inducible factor alpha (Hif1a). Together, these results provide a mechanistic understanding of an important example of developmental heterochrony and exemplify how the maternal environment can regulate timing during embryonic development.