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Utilization of gene knockout approaches in the mouse to elucidate additional functions of smad proteins during mammalian development
| Title: | Utilization of gene knockout approaches in the mouse to elucidate additional functions of smad proteins during mammalian development |
| Author: | Hester, Mark |
| Description: | Smad proteins are the intracellular mediator proteins for TGF-beta, activin, nodal, and BMP signaling molecules. Smad1, 5, and 8 belong to a sub-class that become activated by bone morphogenetic proteins (BMPs), which can multimerize with Smad4 (co-Smad), whereby this complex can translocate into the nucleus to modulate gene transcription. Previous research has shown that Smad1 is important in the formation of the allantois, while Smad4 has been shown to be equally important in the development of extraembryonic tissues. To further analyze the BMP-responsive Smads, the murine Smad8 gene was disrupted utilizing the Cre/loxP system. A Smad8 hypomorphic allele was constructed that contains an in-frame deletion of exon three, removing one third of the MH2 domain and a small portion of the linker region. Although these embryos are phenotypically normal, homozygotes of another allele of Smad8 (Smad83loxP) that contains a neomycin cassette within intron 3, phenocopy an embryonic brain defect observed in roughly 22% of Smad1+/- embryos analyzed at E11.5. Specifically, these embryos exhibited a drastic reduction of hindbrain and midbrain structures. To further characterize the functions of Smad proteins during mammalian development, Smad4 was conditionally deleted within the mouse utilizing the FSP-Cre driver strain. Utilizing this strain eliminates expression of Smad4 in fibroblastic, mesenchymal cell types. Mice depleted for Smad4 utilizing this driver strain exhibit multiple phenotypes such as deformed digits, hair follicle dysplasia, and overall immune and health deficiencies. Histological analysis of Smad4 mutant hair follicles show irregular, enlarged hair follicles, dermal cysts, hyperkeratosis, and utriculi. Further analysis has revealed a defect in mutant hair follicles entering the catagen stage of the hair cycle. The catagen stage is characterized by an apoptosis-driven regression phase of the hair cycle that results in the remodeling of the hair follicle. In addition, increased cell proliferation and decreased apoptosis are observed in mutant hair follicles suggesting a mechanism underlying these enlarged hair follicles. Interestingly, certain developmental processes do not require Smad4 in order to relay BMP and TGF-beta signals into the nucleus to regulate gene transcription, but we have shown its critical requirement in the control of hair follicle growth and cycling. |
| Permanent Link: |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1118656704
http://hdl.handle.net/2374.OX/7007 |
| Date: | 2005 |
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