SummaryNaturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrated that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity while AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.

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Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes - proliferation vs. differentiation and cell death vs. survival1. Here we demonstrate that the loss of epidermal caspase-8, an important mediator of apoptosis2, recapitulates multiple phases of a wound healing response. The epidermal hyperplasia in the caspase-8 null skin is the culmination of signals exchanged between epithelial, mesenchymal, and leukocytic cells. This reciprocal interaction is initiated by the paracrine signaling of interleukin-1α (IL-1α) which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL-1α is induced by a p38 MAPK mediated upregulation of NALP3 leading to inflammasome assembly and caspase-1 activation. Interestingly, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocyte in the stratified epidermis by IL1α-dependent NFκB signaling. Altogether our findings illustrate how the loss of caspase-8 can have an impact beyond programmed cell death to affect the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

In a common theme of organogenesis, certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure. Using hair bud morphogenesis as a paradigm, we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved. We found that transforming growth factor β2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras-mitogen-activated protein kinase (MAPK) pathway in the bud. In the epidermis, Snail misexpression leads to hyperproliferation and a reduction in intercellular adhesion. When E-cadherin is transcriptionally down-regulated, associated adhesion proteins with dual functions in signaling are released from cell-cell contacts, a process which we demonstrate leads to Ras-MAPK activation. These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation, junctional remodeling, and bud formation. This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin.