MPZL3 as a Therapeutically Targetable Mitochondrial Regulator of Sebaceous Gland Homeostasis and Sebum Production - Project Summary Besides the production of sebum, which is essential for epidermal barrier function, skin elasticity, thermoregulation and microbiome management, the sebaceous gland (SG) also exerts important immunological, metabolic and (neuro)endocrine functions. Since dysregulated SG differentiation and sebum production are seen in many skin diseases such as acne vulgaris, scarring alopecia, seborrheic dermatitis and sebaceous tumors, the identification of central new molecular controls of SG differentiation and sebum production will help to pinpoint new targets for therapeutic intervention for these skin diseases. The current translational research project aims to identify myelin protein zero-like 3 (MPZL3) as a novel, therapeutically targetable key regulator of SG homeostasis and sebum production via the control of sebocyte (SB) proliferation and lipogenesis, in both murine and human skin. This project is based on our observation that global knockout (GKO) mice for MPZL3, an essential mitochondrial regulator of epidermal differentiation, show excessive sebum production, persistent SG hyperplasia and SB hyperproliferation. It will be the first to interrogate the regulatory function of MPZL3 in a SG/SB biology context. Based on phenotype similarities between Mpzl3 GKO mice and KO mice for PPARg, a key transcriptional regulator of SG differentiation, the presence of putative PPARg responsive elements in MPZL3 regulatory sequence, and preliminary data showing up-regulated Mpzl3 expression upon PPARg agonist treatment, we hypothesize that MPZL3 functions immediately downstream of PPARg to regulate SB proliferation and differentiation. Aim 1 will identify changes in SG homeostasis and sebum production upon global Mpzl3 deletion. Quantitative (immuno-)histomorpho- metry and qRT-PCR, along with LCM-based RNAseq and pathway analysis will identify critical pathways altered in Mpzl3 GKO skin. These results will be correlated with advanced lipidomics and proteomics analyses by mass spectrometry to identify MPZL3-dependent changes in lipid pathways during SB differentiation. Aim 2 will distinguish epithelia-derived from extra-epithelial, MPZL3-dependent signals that regulate SG function by comparing the SG phenotype in K14-Cre mediated, skin epithelia-specific Mpzl3 epiKO mice with GKO mice. Aim 3 will determine the function of MPZL3 in human SBs and the regulation of MPZL3 function by PPARg using in vitro (human SZ95 SBs), ex vivo (human skin organ culture) and novel human SG 3D organoids, as well as in vivo models (Mpzl3 GKO and epiKO mice). Our studies will provide critical insights into the control of murine and human SG physiology as being, at least in part, mitochondrially regulated via MPZL3. We expect to identify MPZL3 as an innovative, drugable target for skin diseases associated with SG pathology and greatly advance our understanding of the evolutionarily conserved functions of MPZL3 in mammalian skin biology.
