Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro. Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans

Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10−37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.

Our understanding of the cellular mechanisms governing carcinoma invasiveness and metastasis has evolved dramatically over the last several years. The previous emphasis on the epithelial-mesenchymal transition as a driver of the migratory properties of single cells has expanded with the observation that carcinoma cells often invade and migrate collectively as adherent groups. Moreover, recent analyses suggest that circulating tumor cells within the vasculature often exist as multicellular clusters and that clusters more efficiently seed metastatic lesions than single circulating tumor cells. While these observations point to a key role for collective cell migration in carcinoma metastasis, the molecular mechanisms driving collective tumor cell migration remain to be discerned. Wnt/PCP (planar cell polarity) signaling, one of the noncanonical Wnt signaling pathways, mediates collective migratory events such as convergent extension during developmental processes. Wnt/PCP signaling components are frequently dysregulated in solid tumors, and aberrant pathway activation contributes to tumor cell migratory properties. Here we summarize key studies that address the mechanisms by which Wnt/PCP signaling mediate collective cell migration in developmental and tumor contexts. We emphasize Wnt/PCP component localization within migrating cells and discuss how component asymmetry may govern the spatiotemporal control of downstream cytoskeletal effectors to promote collective cell motility.

14Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate 15 development, but its downstream signaling events remain poorly understood. By conducting a large-scale 16 proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a new 17 regulatory target that is degraded upon pathway activation in a b-catenin-independent, ubiquitin-proteasome 18 system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and 19 delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase 20 kinase 3 that regulates Pdzrn3 stability. Genetic epistasis analysis suggests that Pdzrn3 degradation occurs 21 downstream of Dishevelled but independently of Kif26b, a previously identified Wnt5a-Ror-Dishevelled 22 signaling target. Further, we discovered that Pdzrn3 degradation requires Wnt5a-dependent phosphorylation of 23 three residues within its C-terminal LNX3H domain, which is conserved in other homologs and likely functions 24 as a Wnt5a-responsive domain. Collectively, this work establishes a new Wnt5a-Ror signaling cascade 25 involving Pdzrn3 phosphorylation and degradation.26 27

Wnt5a‐Ror signaling is a conserved developmental pathway that regulates morphogenetic processes during vertebral embryonic development, and dysfunction of the pathway causes a number of human disorders, including Robinow syndrome. The mechanisms of Wnt5a‐Ror signaling remain poorly understood. Using a large‐scale proteomic screen, we identified the E3 ubiquitin ligase Pdzrn3 as a new regulatory target that is degraded upon pathway activation in a beta‐catenin independent, ubiquitin‐proteasome system dependent manner. Using this discovery, we developed a flow cytometry‐based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 degradation. Genetic epistasis analysis suggests that Pdzrn3 resides downstream of Dishevelled and independently of Kif26b, a previously identified Wnt5a‐Ror regulatory target. Further, we discovered that Pdzrn3 degradation requires Wnt5a‐dependent phosphorylation of its C‐terminal LNX3H domain, which is conserved in several Pdzrn3 homologs and likely functions as a novel Wnt5a‐responsive domain. Collectively, this work establishes a new Wnt5a‐Ror signaling cascade involving Pdzrn3 phosphorylation and degradation. Support or Funding Information NIH Grant 1R35GM119574