Geminin is required for Hox gene regulation to pattern the developing limb

Dev Biol. 2020 Aug 1;464(1):11-23. doi: 10.1016/j.ydbio.2020.05.007. Epub 2020 May 23.


Development of the complex structure of the vertebrate limb requires carefully orchestrated interactions between multiple regulatory pathways and proteins. Among these, precise regulation of 5' Hox transcription factor expression is essential for proper limb bud patterning and elaboration of distinct limb skeletal elements. Here, we identified Geminin (Gmnn) as a novel regulator of this process. A conditional model of Gmnn deficiency resulted in loss or severe reduction of forelimb skeletal elements, while both the forelimb autopod and hindlimb were unaffected. 5' Hox gene expression expanded into more proximal and anterior regions of the embryonic forelimb buds in this Gmnn-deficient model. A second conditional model of Gmnn deficiency instead caused a similar but less severe reduction of hindlimb skeletal elements and hindlimb polydactyly, while not affecting the forelimb. An ectopic posterior SHH signaling center was evident in the anterior hindlimb bud of Gmnn-deficient embryos in this model. This center ectopically expressed Hoxd13, the HOXD13 target Shh, and the SHH target Ptch1, while these mutant hindlimb buds also had reduced levels of the cleaved, repressor form of GLI3, a SHH pathway antagonist. Together, this work delineates a new role for Gmnn in modulating Hox expression to pattern the vertebrate limb.

Keywords: Geminin; Gene regulation; Hox genes; Limb development; Sonic hedgehog pathway.

Publication types

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

MeSH terms

  • Animals
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology*
  • Geminin / genetics
  • Geminin / metabolism*
  • Gene Expression Regulation, Developmental*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Hindlimb / cytology
  • Hindlimb / embryology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Patched-1 Receptor / genetics
  • Patched-1 Receptor / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Geminin
  • Gmnn protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Hoxd13 protein, mouse
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Shh protein, mouse
  • Transcription Factors