title: Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle.
abstract: The bulbocavernosus (BC) is a sexually dimorphic muscle observed only in males. Androgen receptor knockout mouse studies show the loss of BC formation. This suggests that androgen signaling plays a vital role in its development. Androgen has been known to induce muscle hypertrophy through satellite cell activation and myonuclei accretion during muscle regeneration and growth. Whether the same mechanism is present during embryonic development is not yet elucidated. To identify the mechanism of sexual dimorphism during BC development, the timing of morphological differences was first established. It was revealed that the BC was morphologically different between male and female mice at embryonic day (E) 16.5. Differences in the myogenic process were detected at E15.5. The male BC possesses a higher number of proliferating undifferentiated myoblasts. To identify the role of androgen signaling in this process, muscle-specific androgen receptor (AR) mutation was introduced, which resulted in no observable phenotypes. Hence, the expression of AR in the BC was examined and found that the AR did not colocalize with any muscle markers such as Myogenic differentiation 1, Myogenin, and paired box transcription factor 7. It was revealed that the mesenchyme surrounding the BC expressed AR and the BC started to express AR at E15.5. AR mutation on the nonmyocytic cells using spalt-like transcription factor 1 (Sall1) Cre driver mouse was performed, which resulted in defective BC formation. It was revealed that the number of proliferating undifferentiated myoblasts was reduced in the Sall1 Cre:AR(L-/Y) mutant embryos, and the adult mutants were devoid of BC. The transition of myoblasts from proliferation to differentiation is mediated by cyclin-dependent kinase inhibitors. An increased expression of p21 was observed in the BC myoblast of the Sall1 Cre:AR(L-/Y) mutant and wild-type female. Altogether this study suggests that the nonmyocytic AR may paracrinely regulate the proliferation of myoblast possibly through inhibiting p21 expression in myoblasts of the BC.
authors.affiliation: Department of Developmental Genetics (L.A.I., K.S., Y.S., A.M., A.O., G.Y.), Institute of Advanced Medicine, and Department of Biology, Wakayama Medical University (WMU), Wakayama 641-8509, Japan; Graduate School of Pharmaceutical Sciences (L.A.I., Y.S.), Division of Reproductive Engineering (N.N.), Center for Animal Resources and Development, Department of Kidney Development (R.N.), Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-8555, Japan; Division of Integrative Pathophysiology (Y.I.), Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime 791-0295, Japan; School of Biological Sciences and Institute for Cardiovascular and Metabolic Research (P.V.), University of Reading, Reading RG6 6UR, United Kingdom; and Institute of Anatomy (P.V.), First Faculty of Medicine, Charles University, 128 00 Prague 2, Czech Republic.
authors.forename: Lerrie Ann
authors.initials: LA
authors.lastname: Ipulan
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Aki
authors.initials: A
authors.lastname: Murashima
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Akiko
authors.initials: A
authors.lastname: Omori
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.forename: Petr
authors.initials: P
authors.lastname: Valasek
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D009132:Muscles / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010502:Perineum / Q000196:embryology; D011247:Pregnancy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D011944:Receptors, Androgen; C491254:Sall1 protein, mouse; D014157:Transcription Factors
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