Asymmetric Cell Division in the Skin

Abstract

An asymmetric cell division (ACD) is defined as a division that gives rise to two daughter cells with different fates. It is the most common type of division during development. Analogous to Drosophila neuroblasts, proteins involved in ACD such as Insc and LGN are found to be asymmetrically localized during perpendicular cell divisions in mammalian skin, suggesting that the cutaneous tissue homeostasis may be controlled by using similar mechanisms. Most cell divisions in the basal layer of the skin are perpendicular to the basal membrane (BM), but when a skin tumor is formed, most cell divisions would become parallel to the BM. Previous studies in our lab have shown that regressing skin tumor caused by β-catenin depletion have increased perpendicular cell divisions accompanied by reduced stem cell numbers and enhanced mTrim2 expression. Furthermore, induced expression of mTRIM2 in skin tumors led to tumor regression. Taken together, this suggests that progenitor cells in the basal layer of the epidermis may use vertical ACDs to maintain progenitor cell number while using horizontal SCDs to expand progenitor cell number and mTrim2 may function as a cell fate determinant in skin. To validate the hypothesis that vertical divisions of basal keratinocytes to the BM are ACDs, I utilized light sheet based fluorescence microscopy (LSFM) to perform the time lapse recording of murine embryonic skin development between E14.5 and E17.5 and to monitor individual dividing cells and to track their fates after division. For visualizing the dividing cells, protein localization and differentiating cells, I have generated several transgenic mouse lines and combined them together. My study showed that ACD of basal keratinocytes can be either vertical or horizontal to the BM and divisions in the suprabasal layer can be both ACDs and SCDs. To study the potential function of mTRIMs in skin, I generated the knock-out (KO) mice. Neither mTrim2 KO, mTrim3 KO or mTrim32 KO mice showed any phenotype in skin, therefore I combined these mice to generate mTrim2/3 double KO and mTrim2/3/32 triple KO mice. Still, no skin phenotype was observed in these mice, indicating that mTrim2/3/32 might not function as a cell fate determinant in skin.