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

Abstract

1 2 This work identifies a new role for Geminin in mouse limb development. Geminin is a nuclear 3 protein that regulates gene expression to control several other aspects of vertebrate development. 4 5 Abstract 6 7 Development of the complex structure of the vertebrate limb requires carefully orchestrated 8 interactions between multiple regulatory pathways and proteins. Among these, precise regulation 9 of 5' Hox transcription factor expression is essential for proper limb bud patterning and elaboration 10 of distinct limb skeletal elements. Here, we identified Geminin (Gmnn) as a novel regulator of this 11 process. A conditional model of Gmnn deficiency resulted in loss or severe reduction of forelimb 12 skeletal elements, while both the forelimb autopod and hindlimb were unaffected. 5' Hox gene 13 expression expanded into more proximal and anterior regions of the embryonic forelimb buds in 14 this Gmnn-deficient model. A second conditional model of Gmnn deficiency instead caused a 15 similar but less severe reduction of hindlimb skeletal elements and hindlimb polydactyly, while not 16 affecting the forelimb. An ectopic posterior SHH signaling center was evident in the anterior 17 hindlimb bud of Gmnn-deficient embryos in this model. This center ectopically expressed Hoxd13, 18 the HOXD13 target Shh, and the SHH target Ptch1, while these mutant hindlimb buds also had 19 reduced levels of the cleaved, repressor form of GLI3, a SHH pathway antagonist. Together, this 20 work delineates a new role for Gmnn in modulating Hox expression to pattern the vertebrate limb.

MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency

“…While reduced growth is an almost universally observed association, additional features in MGORS are related to anomalies in cartilagenesis or skeletogenesis, which could be linked to recently described cellular interactions between SHH or HOX genes and DNA replication initiation factors [43,44]. Conversely, multiple members of the preIC and the replisome are involved in various aspects of immune system development and adrenal functioning [37], for which the developmental pathophysiology remains unclear.…”