RT Journal Article SR Electronic T1 Geminin is required for Hox gene regulation to pattern the developing limb JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.07.896472 DO 10.1101/2020.01.07.896472 A1 Emily M.A. Lewis A1 Savita Sankar A1 Caili Tong A1 Ethan Patterson A1 Laura E. Waller A1 Paul Gontarz A1 Bo Zhang A1 David M. Ornitz A1 Kristen L. Kroll YR 2020 UL http://biorxiv.org/content/early/2020/01/08/2020.01.07.896472.abstract AB 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.Summary This work identifies a new role for Geminin in mouse limb development. Geminin is a nuclear protein that regulates gene expression to control several other aspects of vertebrate development.