Unknown,Transcriptomics,Genomics,Proteomics

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Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [mixed stage]

ABSTRACT: Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=3 WT and KO (each sample contain dissected dental tissues from 3 mice combined)

ORGANISM(S): Mus musculus

SUBMITTER: Yuko Oda

PROVIDER: E-GEOD-50503 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cell fates are defined by specific transcriptional program. Previously, we developed a unique stem cell regeneration mouse model, in which transcriptional program for ectoderm organs such as tooth and skin is switched. Genomic deletion of one subunit of Mediator complex, Med1, resulted in defective enamel regeneration, in which dental stem cells were inhibited from undergoing transcriptional program for dental fate. In stead, they exerted skin program for both hair and epidermis, and post-natally regenerate ectopic hairs in the incisors. Here, we report that Med1 also modulates epidermal and hair cell fates in the skin. Med1 ablation further enhanced epidermal and sebocyte fates, and accelerated injury induced epidermal regeneration. However, it blunted hair fate resulting in hair loss in the skin. Ablation of Med1 increased the number of isthmus stem cells and epidermal stem cells, which regenerate epidermis during cutaneous wound healing process. Med1 deficiency also constitutively activated these stem cells and increased their proliferation. Microarray profiling indicated that Med1 deletion causes activation of β-catenin and suppression of TGFβ signaling. Med1 deficiency induced the expression of β-catenin target genes to control cell fate and proliferation. It also decreased TGFβ expression in interfollicular epidermis. Med1 deficiency increased the proliferation and migration of epidermal cells, and induced nuclear translocation of β-catenin, and decreased TGFβ1 expression in vitro. Our finding together with previous observations demonstrated that Med1 governs ectoderm cell fate in both tooth and skin. Med1 ablation blunts hair fate but induces epidermal and sebocyte cell fates to accelerated injury induced epidermal regeneration in the skin. Accelerated regeneration is derived from constitutive activation of epidermal stem cells accompanied with increased proliferation and migration of their progeny by balancing of β-catenin induced growth promoting and TGFβ mediated growth inhibitory activities in the skin.

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Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [mixed stage]

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