Multipotent skin stem cells give rise to epidermis and its appendages, including the hair follicle. The Lef-1/Tcf family of Wnt-regulated transcription factors plays a major role in specification of the hair shaft, but little is known about how the equally important hair channel, the inner root sheath (IRS), develops in concert to shape and guide the hair. In a microarray screen to search for transcriptional regulators of hair follicle morphogenesis, we identified GATA-3, a key regulator of T-cell lineage determination. Surprisingly, this transcription factor is essential for stem cell lineage determination in skin, where it is expressed at the onset of epidermal stratification and IRS specification in follicles. GATA-3-null/lacZ knock-in embryos can survive up to embryonic day 18.5 (E18.5), when they fail to form the IRS. Skin grafting unveiled additional defects in GATA-3-null hairs and follicles. IRS progenitors failed to differentiate, whereas cortical progenitors differentiated, but produced an aberrant hair structure. Curiously, some GATA-3-null progenitor cells expressed mixed IRS and hair shaft markers. Taken together, these findings place GATA-3 with Lef-1/Wnts at the crossroads of the IRS versus hair shaft cell fate decision in hair follicle morphogenesis. This newfound function for GATA-3 in skin development strengthens the parallels between the differentiation programs governing hair follicle and lymphocyte differentiation.

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One of the essential components of a phosphatase that specifically dephosphorylates the Saccharomyces cerevisiae RNA polymerase II (RPII) large subunit C-terminal domain (CTD) is a novel polypeptide encoded by an essential gene termed FCP1. The Fcp1 protein is localized to the nucleus, and it binds the largest subunit of the yeast general transcription factor IIF (Tfg1). In vitro, transcription factor IIF stimulates phosphatase activity in the presence of Fcp1 and a second complementing fraction. Two distinct regions of Fcp1 are capable of binding to Tfg1, but the C-terminal Tfg1 binding domain is dispensable for activity in vivo and in vitro. Sequence comparison reveals that residues 173-357 of Fcp1 correspond to an amino acid motif present in proteins of unknown function predicted in many organisms.Promoter-dependent transcription by RNA polymerase II (RPII) requires six general transcription factors (reviewed in ref.

disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE To develop recommendations for the care of adults with EMPD.EVIDENCE REVIEW A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGSThe key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. ( 5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.CONCLUSIONS AND RELEVANCE Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

AP-2 transcription factors have been implicated in epidermal biology, but their functional significance has remained elusive. Using conditional knockout technology, we show that AP-2α is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2α exhibits elevated expression of the epidermal growth factor receptor (EGFR) in the differentiating layers, resulting in hyperproliferation when the receptors are activated. Chromatin immunoprecipitation and promoter activity assays identify EGFR as a direct target gene for AP-2α repression, and, in the absence of AP-2α, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2α in governing EGFR gene transcription as cells exit the basal layer and withdraw from the cell cycle. These results provide insights into why elevated AP-2α levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2α and elevated EGFR proteins.

Mohs micrographic surgery is safe, with a very low rate of adverse events, an exceedingly low rate of serious adverse events, and an undetectable mortality rate. Common complications include infections, followed by impaired wound healing and bleeding. Bleeding and wound-healing issues are often associated with preexisting anticoagulation therapy, which is nonetheless managed safely during MMS. We are not certain whether the small effects seen with the use of sterile gloves and antiseptics and antibiotics are clinically significant and whether wide-scale practice changes would be cost-effective given the small risk reductions.

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IMPORTANCE Microcystic adnexal carcinoma (MAC) occurs primarily in older adults of white race/ethnicity on sun-exposed skin of the head and neck. There are no formal guiding principles based on expert review of the evidence to assist clinicians in providing the highest-quality care for patients. OBJECTIVE To develop recommendations for the care of adults with MAC.EVIDENCE REVIEW A systematic review of the literature (1990 to June 2018) was performed using MEDLINE, Embase, Web of Science, and the Cochrane Library. The keywords searched were microcystic adnexal carcinoma, sclerosing sweat gland carcinoma, sclerosing sweat duct carcinoma, syringomatous carcinoma, malignant syringoma, sweat gland carcinoma with syringomatous features, locally aggressive adnexal carcinoma, and combined adnexal tumor. A multidisciplinary expert committee critically evaluated the literature to create recommendations for clinical practice. Statistical analysis was used to estimate optimal surgical margins.