Studies On The Function Of Mouse Dapper2 Gene Using Gene Knockout

Transforming growth factor (TGF-β) signals regulate a variety of cellular events and play important roles in embryonic development. Members of the Dapper (Dpr)/Dact family play roles in regulating distinct signaling pathways, including TGF-β/Nodal as well as canonical and noncanonical Wnt pathways. Three mouse Dpr genes, Dpr1-Dpr3, are expressed in mouse embryos and in distinct adult tissues, particularly in the brain. It has been demonstrated that zebrafish Dpr2 modulates Nodal/TGF-βsignals by promoting lysosomal degradation of their receptors and inhibits mesoderm induction in zebrafish embryos. Mouse Dpr2 is able to antagonize TGF-β? signaling in vitro and ectopic expression in zebrafish embryos also results in reduction of mesoderm gene expression. However, functions of mDpr2 in vivo have not been reported.In this study, Dpr2-deficient mice were generated by gene knockout approach. Dpr2 knockout (Dpr2-/-) embryos developed normally and they were alive at birth. Like wild-type blastocysts, the isolated Dpr2-/- E3.5 blastocysts hatched from the zona pellucida, and had normal Outgrowth. Postnatal Dpr2-/- mice were able to grow up and the adults were fertile. The distribution of Dpr2 transcripts in subregions of adult brain of mice was examined in details. Dpr2 appears to be highly expressed in the cerebral cortex, hippocampus, thalamus and medulla oblongata. However, histological analyses revealed that Dpr2-/- mice had normal brain morphology; their neural stem cells showed proliferative activity similar to those of their wild-type littermates. Dpr2 was found to be highly expressed in epidermal keratinocytes and in hair follicles of adult mice, and its deficiency resulted in the accelerated re-epithelialization during cutaneous wound healing. Furthermore, loss of Dpr2 function enhanced the responses of keratinocytes to TGF-βstimulation; and TGF-βsignals promoted keratinocytes migration by regulating the expression of specific integrin genes.Taken together, these data suggest that Dpr2 is dispensable for mouse embryonic development, postnatal growth and brain formation. But, Dpr2 plays an inhibitory role in the re-epithelialization of adult skin wounds by attenuating TGF-βsignaling.