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Loss of Adgra3 causes obstructive azoospermia with high penetrance in male mice

Nybo, Maja L; Kvam, Jone M; Nielsen, John E; Frederiksen, Hanne; Spiess, Katja; Jensen, Kristian H R; Gadgaard, Sarina; Walser, Anna L S; Thomsen, Jesper S; Cowin, Pamela; Juul, Anders; Jensen, Martin B; Rosenkilde, Mette M
The adhesion receptor ADGRA3 (GPR125) is a known spermatogonial stem cell marker, but its impact on male reproduction and fertility has not been examined. Using a mouse model lacking Adgra3 (Adgra3-/- ), we show that 55% of the male mice are infertile from puberty despite having normal spermatogenesis and epididymal sperm count. Instead, male mice lacking Adgra3 exhibited decreased estrogen receptor alpha expression and transient dilation of the epididymis. Combined with an increased estradiol production, this indicates a post-pubertal hormonal imbalance and fluid retention. Dye injection revealed a blockage between the ejaculatory duct and the urethra, which is rare in mice suffering from infertility, thereby mimicking the etiologies of obstructive azoospermia found in human male infertility. To summarize, male reproductive tract development is dependent on ADGRA3 function that in concert with estrogen signaling may influence fluid handling during sperm maturation and storage.
PMID: 36688818
ISSN: 1530-6860
CID: 5401922

Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency

Spina, Elena; Simundza, Julia; Incassati, Angela; Chandramouli, Anupama; Kugler, Matthias C; Lin, Ziyan; Khodadadi-Jamayran, Alireza; Watson, Christine J; Cowin, Pamela
Gpr125 is an orphan G-protein coupled receptor, with homology to cell adhesion and axonal guidance factors, that is implicated in planar polarity and control of cell movements. By lineage tracing we demonstrate that Gpr125 is a highly specific marker of bipotent mammary stem cells in the embryo and of multiple long-lived unipotent basal mammary progenitors in perinatal and postnatal glands. Nipple-proximal Gpr125+ cells express a transcriptomic profile indicative of chemo-repulsion and cell movement, whereas Gpr125+ cells concentrated at invasive ductal tips display a hybrid epithelial-mesenchymal phenotype and are equipped to bind chemokine and growth factors and secrete a promigratory matrix. Gpr125 progenitors acquire bipotency in the context of transplantation and cancer and are greatly expanded and massed at the pushing margins of short latency MMTV-Wnt1 tumors. High Gpr125 expression identifies patients with particularly poor outcome within the basal breast cancer subtype highlighting its potential utility as a factor to stratify risk.
PMID: 35302059
ISSN: 2041-1723
CID: 5181672

Gpr125 identifies myoepithelial progenitors at tips of lacrimal ducts and is essential for tear film [PrePrint]

Spina, Elena; Handlin, Rebecca; Simundza, Julia; Incassati, Angela; Faiq, Muneeb; Sainulabdeen, Anoop; Chan, Kevin C; Cowin, Pamela
Gpr125, encoded by Adgra3, is an orphan adhesion G-protein coupled receptor (aGPCR) implicated in modulating Wnt signaling and planar polarity. Here we establish both physiological and pathological roles for Gpr125. We show that mice lacking Gpr125 or its signaling domains display an ocular phenotype with many hallmarks of human dry eye syndrome. These include squinting, abnormal lacrimation, mucus accumulation, swollen eyelids and inflammatory infiltration of lacrimal and meibomian glands. Utilizing a Gpr125-β-gal reporter and scRNAseq, we identify Gpr125 expression in a discrete population of cells located at the tips of migrating embryonic lacrimal ducts. By lineage tracing we show these cells function as progenitors of the adult lacrimal myoepithelium. Beyond defining an essential role for Gpr125 in tear film and identifying its utility as a marker of lacrimal progenitors, this study implicates Gpr125 in the etiology of blepharitis and dry eye syndrome, and defines novel animal models of these common maladies
ORIGINAL:0015379
ISSN: 2692-8205
CID: 5069122

Embryonic mammary gland development

Spina, Elena; Cowin, Pamela
Embryonic mammary gland development involves the formation of mammary placodes, invagination of flask-shaped mammary buds and development of miniature bi-layered ductal trees. Currently there is a good understanding of the factors that contribute to ectodermal cell movements to create these appendages and of pathways that lead to mammary specification and commitment. Gene expression profiles of early bipotent mammary stem cells populations as well as cell surface proteins and transcription factors that promote the emergence of unipotent progenitors have been identified. Analyses of these populations has illuminated not only embryonic mammary development, but highlighted parallel processes in breast cancer. Here we provide an overview of the highly conserved pathways that shape the embryonic mammary gland. Understanding the dynamic signaling events that occur during normal mammary development holds considerable promise to advance attempts to eliminate cancer by restoring differentiative signals.
PMID: 33472760
ISSN: 1096-3634
CID: 4760642

Highlighting Kathleen Green and Mario Delmar, Guest Editors of Special Issue (part 2): Junctional Targets of Skin and Heart Disease

Cowin, Pamela
Abstract Cell Communication and Adhesion has been fortunate to enlist two pioneers of epidermal and cardiac cell junctions, Kathleen Green and Mario Delmar, as Guest Editors of a two part series on junctional targets of skin and heart disease. Part 2 of this series begins with an overview from Dipal Patel and Kathy Green comparing epidermal desmosomes to cardiac area composita junctions, and surveying the pathogenic mechanisms resulting from mutations in their components in heart disease. This is followed by a review from David Kelsell on the role of desmosomal mutation in inherited syndromes involving skin fragility. Agnieszka Kobeliak discusses how structural deficits in the epidermal barrier intersect with the NFkB signaling pathway to induce inflammatory diseases such as psoriasis and atopic dermatitis. Farah Sheikh reviews the specialized junctional components in cardiomyocytes of the cardiac conduction system and Robert Gourdie discusses how molecular complexes between sodium channels and gap junction proteins within the perijunctional microdomains within the intercalated disc facilitate conduction. Glenn Radice evaluates the role of N-cadherin in heart. Andre Kleber and Chris Chen explore new approaches to study junctional mechanotransduction in vitro with a focus on the effects of connexin ablation and the role of cadherins, respectively. To complement this series of reviews, we have interviewed Werner Franke, whose systematic documentation the tissue-specific complexity of desmosome composition and pioneering discovery of the cardiac area composita junction greatly facilitated elucidation of the role of desmosomal components in the pathophysiology of human heart disease.
PMID: 24854768
ISSN: 1543-5180
CID: 1013482

Bringing law and order to the cytoskeleton and cell junctions: An interview with Werner Franke

Cowin, Pamela
PMID: 24854769
ISSN: 1543-5180
CID: 1013492

Highlights from special issue: junctional targets of skin and heart diseases

Delmar, Mario; Green, Kathleen; Cowin, Pamela
In this issue, guest editors Kathy Green and Mario Delmar, who are leaders in the fields of epidermal desmosomes and heart intercalated discs respectively, have joined forces to collate a two-part series of reviews focused on junctional proteins and genes that are targets of skin and heart diseases.
PMID: 24460196
ISSN: 1543-5180
CID: 833232

Adhesion g-protein-coupled receptors: elusive hybrids come of age

Simundza, Julia; Cowin, Pamela
Abstract Adhesion G-protein-coupled receptors (GPCRs) are the most recently identified and least understood subfamily of GPCRs. Adhesion GPCRs are characterized by unusually long ectodomains with adhesion-related repeats that facilitate cell- cell and cell-cell matrix contact, as well as a proteolytic cleavage site-containing domain that is a structural hallmark of the family. Their unusual chimeric structure of adhesion-related ectodomain with a seven-pass transmembrane domain and cytoplasmic signaling makes these proteins highly versatile in mediating cellular signaling in response to extracellular adhesion or cell motility events. The ligand binding and cytoplasmic signaling modes for members of this family are beginning to be elucidated, and recent studies have demonstrated critical roles for Adhesion GPCRs in planar polarity and other important cell-cell and cell-matrix interactions during development and morphogenesis, as well as heritable diseases and cancer.
PMCID:4165398
PMID: 24229322
ISSN: 1543-5180
CID: 681042

Highlighting Young Investigators: Guest Editor Ramanuj DasGupta Ram DasGupta: Pushing the boundaries of beta-catenin signaling and drug development

Cowin, Pamela
Abstract From generating the TOP-GAL mouse to pioneering high-throughput RNAi, and small molecule chemical genetic screens in Drosophila and mammalian cells, Ram DasGupta has consistently developed innovative technological tools of immense value to the fields in which he has chosen to work.
PMID: 24274117
ISSN: 1543-5180
CID: 681052

Leaders in cell adhesion: an interview with richard hynes, pioneer of cell-matrix interactions

Cowin, Pamela
Abstract On a recent visit Richard O Hynes, FRS, HHMI, Daniel K. Ludwig Professor for Cancer Research at the Koch Institute for Integrative Cancer Research, MIT, graciously agreed to be interviewed in person for the first in Cell Communication and Adhesion's series on "Leaders in Cell Adhesion". In this interview we discussed three things: 1) the early role of family, mentors, and luck on his career path; 2) his major discoveries of fibronectin, integrins and the evolution of extracellular matrix proteins; and 3) his role in, and thoughts on, current science policy. This interview reveals his characteristic calmness and infectious optimism, his spontaneous and down to earth sense of humor, and his great ability to place scientific questions in perspective. The interview, carried out on April 30(th) 2013 is reported here verbatim with only minor editing for clarity.
PMID: 24274118
ISSN: 1543-5180
CID: 681062