title: Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme.
abstract: Parathyroid hormone-related protein (PTHrP) regulates cell fate and specifies the mammary mesenchyme during embryonic development. Loss of PTHrP or its receptor (Pthr1) abolishes the expression of mammary mesenchyme markers and allows mammary bud cells to revert to an epidermal fate. By contrast, overexpression of PTHrP in basal keratinocytes induces inappropriate differentiation of the ventral epidermis into nipple-like skin and is accompanied by ectopic expression of Lef1, β-catenin and other markers of the mammary mesenchyme. In this study, we document that PTHrP modulates Wnt/β-catenin signaling in the mammary mesenchyme using a Wnt signaling reporter, TOPGAL-C. Reporter expression is completely abolished by loss of PTHrP signaling and ectopic reporter activity is induced by overexpression of PTHrP. We also demonstrate that loss of Lef1, a key component of the Wnt pathway, attenuates the PTHrP-induced abnormal differentiation of the ventral skin. To characterize further the contribution of canonical Wnt signaling to embryonic mammary development, we deleted β-catenin specifically in the mammary mesenchyme. Loss of mesenchymal β-catenin abolished expression of the TOPGAL-C reporter and resulted in mammary buds with reduced expression of mammary mesenchyme markers and impaired sexual dimorphism. It also prevented the ectopic, ventral expression of mammary mesenchyme markers caused by overexpression of PTHrP in basal keratinocytes. Therefore, we conclude that a mesenchymal, canonical Wnt pathway mediates the PTHrP-dependent specification of the mammary mesenchyme.
authors.affiliation: Department of Biological Sciences, Boise State University, Boise, ID 83725,  USA.
authors.forename: Minoti
authors.initials: M
authors.lastname: Hiremath
authors.forename: Pamela
authors.initials: P
authors.lastname: Dann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fischer
authors.forename: Daniela
authors.initials: D
authors.lastname: Butterworth
authors.forename: Kata
authors.initials: K
authors.lastname: Boras-Granic
authors.forename: Julie
authors.initials: J
authors.lastname: Hens
authors.forename: Joshua
authors.initials: J
authors.lastname: Van Houten
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: John
authors.initials: J
authors.lastname: Wysolmerski
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018016:Receptors, Parathyroid Hormone / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D019699:Thrombospondins / Q000378:metabolism; D051153:Wnt Proteins / Q000096:biosynthesis / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D044162:Parathyroid Hormone-Related Protein; C518903:RSPO1 protein, mouse; D018016:Receptors, Parathyroid Hormone; D019699:Thrombospondins; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse; D051176:beta Catenin