title: Gli activity is critical at multiple stages of embryonic mammary and nipple development.
abstract: Gli3 is a transcriptional regulator of Hedgehog (Hh) signaling that functions as a repressor (Gli3(R)) or activator (Gli3(A)) depending upon cellular context. Previously, we have shown that Gli3(R) is required for the formation of mammary placodes #3 and #5. Here, we report that this early loss of Gli3 results in abnormal patterning of two critical regulators: Bmp4 and Tbx3, within the presumptive mammary rudiment (MR) #3 zone. We also show that Gli3 loss leads to failure to maintain mammary mesenchyme specification and loss of epithelial Wnt signaling, which impairs the later development of remaining MRs: MR#2 showed profound evagination and ectopic hairs formed within the presumptive areola; MR#4 showed mild invagination defects and males showed inappropriate retention of mammary buds in Gli3(xt/xt) mice. Importantly, mice genetically manipulated to misactivate Hh signaling displayed the same phenotypic spectrum demonstrating that the repressor function of Gli3(R) is essential during multiple stages of mammary development. In contrast, positive Hh signaling occurs during nipple development in a mesenchymal cuff around the lactiferous duct and in muscle cells of the nipple sphincter. Collectively, these data show that repression of Hh signaling by Gli3(R) is critical for early placodal patterning and later mammary mesenchyme specification whereas positive Hh signaling occurs during nipple development.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, United States of America ; The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Anupama
authors.initials: A
authors.lastname: Chandramouli
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hatsell
authors.forename: Alicia
authors.initials: A
authors.lastname: Pinderhughes
authors.forename: Lisa
authors.initials: L
authors.lastname: Koetz
authors.forename: Pamela
authors.initials: P
authors.lastname: Cowin
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology*; D018859:Hair Follicle / Q000196:embryology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009558:Nipples / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C498520:Gli1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D000071676:Zinc Finger Protein GLI1