Stem cells in ectodermal development

Tissue-specific stem cells sustain organs for a lifetime through self-renewal and generating differentiated progeny. Although tissue stem cells are established during organogenesis, the precise origin of most adult stem cells in the developing embryo is unclear. Mammalian skin is one of the best-studied epithelial systems containing stem cells to date, however the origin of most of the stem cell populations found in the adult epidermis is unknown. Here, we try to recapitulate the emergence and genesis of an ectodermal stem cell during development until the formation of an adult skin. We ask whether skin stem cells share key transcriptional regulators with their embryonic counterparts and discuss whether embryonic-like stem cells may persist through to adulthood in vivo

Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1

Glutamate receptor-interacting protein 1 (GRIP1) is an adaptor protein composed of seven PDZ (postsynaptic density-95/Discs large/zona occludens-1) domains, capable of mediating diverse protein–protein interactions. GRIP1 has been implicated in the regulation of neuronal synaptic function, but its physiologic roles have not been defined in vivo. We find that elimination of murine GRIP1 results in embryonic lethality. GRIP1(−/−) embryos develop abnormalities of the dermo-epidermal junction, resulting in extensive skin blistering around day 12 of embryonic life. Ultra-structural characterization of the blisters (or bullae) revealed cleavage of the dermo-epidermal junction below the lamina densa, an alteration reminiscent of the dystrophic form of human epidermolysis bullosa. Blisters were also observed in the lateral ventricle of the brain and in the meninges covering the cerebral cortex. These genetic data suggest that the GRIP1 scaffolding protein is required for the formation and integrity of the dermo-epidermal junction and reveal the importance of PDZ domains in the organization of supramolecular structures essential for mammalian embryonic development

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

The transcription factor Ets1 is normally expressed in the proliferative layer of stratified epithelium, but expression of Ets1 is significantly upregulated in squamous cell carcinomas. How elevated levels of Ets1 impact tumor initiation and progression is not well understood. To determine the biological consequences of overexpression of Ets1, we developed a transgenic mouse model that allows induction of Ets1 expression in keratinocytes of stratified epithelium in a regulatable fashion. Induction of Ets1 during embryonic development results in a dramatic alteration in epidermal structure and function by suppressing the expression of multiple stratum corneum constituents, while at the same time inducing expression of EGF ligands, AP1 transcription factors and matrix metalloproteases. Interestingly, expression of certain immune-related genes, including defensins, chemokines and cytokines was increased as well, suggesting a possible role for immune dysregulation in the promotion of squamous dysplasia. Experiments using cultured mouse keratinocytes indicate that Ets1 can induce expression of some of these mediators in a cell-intrinsic fashion. Collectively, our data reveal that elevated expression of Ets1 has a much broader array of pro-tumorigenic effects on epithelial cells than previously appreciated