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Laurence S. Baskin - One of the best experts on this subject based on the ideXlab platform.
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development of the human penis and clitoris
Differentiation, 2018Co-Authors: Laurence S. Baskin, Adriane Sinclair, Dylan Isaacson, Maya Overland, Joel Shen, Yi Li, Gerald R CunhaAbstract:Abstract The human penis and clitoris develop from the ambisexual Genital Tubercle. To compare and contrast the development of human penis and clitoris, we used macroscopic photography, optical projection tomography, light sheet microscopy, scanning electron microscopy, histology and immunohistochemistry. The human Genital Tubercle differentiates into a penis under the influence of androgens forming a tubular urethra that develops by canalization of the urethral plate to form a wide diamond-shaped urethral groove (opening zipper) whose edges (urethral folds) fuse in the midline (closing zipper). In contrast, in females, without the influence of androgens, the vestibular plate (homologue of the urethral plate) undergoes canalization to form a wide vestibular groove whose edges (vestibular folds) remain unfused, ultimately forming the labia minora defining the vaginal vestibule. The neurovascular anatomy is similar in both the developing human penis and clitoris and is the key to successful surgical reconstructions.
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New Insights on the Morphology of Adult Mouse Penis1
2016Co-Authors: Laurence S. BaskinAbstract:The adult mouse penis represents the end point of masculine sex differentiation of the embryonic Genital Tubercle and contains bone, cartilage, the urethra, erectile bodies, several types of epithelium, and many individual cell types arrayed into specific anatomical structures. Using contemporary high-reso-lution imaging techniques, we sought to provide new insights to the current description of adult mouse penile morphology to enable understanding of penile abnormalities, including hypo-spadias. Examination of serial transverse and longitudinal sections, scanning electron microscopy, and three-dimensional (3D) reconstruction provided a new appreciation of the individual structures in the adult mouse penis and their 3D interrelationships. In so doing, we discovered novel paired erectile bodies, the male uroGenital mating protuberance (MUMP), and more accurately described the urethral meatus. These morphological observations were quantified by morpho-metric analysis and now provide accurate morphological end points of sex differentiation of mouse penis that will be the foundation of future studies to identify normal and abnormal penile development. developmental biology, differentiation, external Genitalia, male reproductive tract, os penis, penile urethra, penis, prepuce, sex differentiatio
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morphology of mouse external Genitalia implications for a role of estrogen in sexual dimorphism of the mouse Genital Tubercle
The Journal of Urology, 2010Co-Authors: Jennifer H Yang, Gerald R Cunha, Julia Menshenina, Ned J Place, Laurence S. BaskinAbstract:Purpose: We examined the role of androgens and estrogens in mammalian sexual differentiation by morphological characterization of adult wt and mutant mouse external Genitalia. We tested the hypothesis that external Genitalia development depends on androgen and estrogen action.Materials and Methods: We studied serial sections of the external Genitalia of the CD-1 and C57BL6 wt strains of adult mice (Charles River Laboratories, Wilmington, Massachusetts). We recorded linear measurements of key structures in each specimen, including the urethra, erectile tissue, bone and cartilage. We used similar methodology to analyze mice mutant for estrogen receptor α (αERKO) and androgen receptor (XTfm/Y) (Jackson Laboratory, Bar Harbor, Maine).Results: Morphology in XTfm/Y adult murine external Genitalia was remarkably similar to that in wt females. Bone and clitoral length was similar in wt females and XTfm/Y mice. Conversely the αERKO clitoris was 59% longer and bone length in αERKO females was many-fold longer than ...
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Estrogen effects on fetal penile and urethral development in organotypic mouse Genital Tubercle culture.
The Journal of urology, 2009Co-Authors: Zhong Wang, Hao Wang, Juan Zhou, Benchun Liu, Laurence S. BaskinAbstract:Purpose: We developed an organotypic Genital Tubercle culture system in vitro and used it to investigate the direct effects of the hyperestrogenic state on fetal mouse penile and urethral development.Materials and Methods: Genital Tubercles were dissected from embryonic day 14.5 C57B/L6 male mouse fetuses and cultured using an air-liquid interface on a microporous membrane support soaked in synthetic medium. Cultures were separated into 4 groups. Groups 1 to 3 were supplied with 10 nM dihydrotestosterone, estradiol and 10 nM dihydrotestosterone plus estradiol, respectively. Group 4 was cultured in hormone-free medium. After 36 to 72-hour culture morphological, histological, proliferation, apoptosis, androgen signaling and activating transcription factor 3 analyses were done.Results: The physiological concentration of 10 nM dihydrotestosterone was essential for Genital Tubercle growth in vitro. Androgen induced growth and urethral development were significantly suppressed by high dose estrogen. Concurrentl...
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Progesterone receptors in the developing Genital Tubercle: implications for the endocrine disruptor hypothesis as the etiology of hypospadias.
The Journal of urology, 2007Co-Authors: Koray Agras, Yoshiyuki Shiroyanagi, Laurence S. BaskinAbstract:Purpose: In fetal mice Genital Tubercles the ontogenetic expression of progesterone receptors and the effect of in utero estrogen and testosterone exposure were investigated.Materials and Methods: To evaluate ontogenetic progesterone receptor expression Genital Tubercles from untreated fetuses at gestational days 12, 14, 16 and 18, and newborn pups were prepared for real-time reverse transcriptase-polymerase chain reaction or immunohistochemistry. To evaluate estrogen and testosterone effects pregnant dams were gavaged once daily with corn oil (vehicle), ethinyl estradiol or testosterone propionate from gestational days 12 through 17. At gestational day 19 the Genital Tubercles of delivered fetuses were harvested for morphological examination and then pooled for real-time reverse transcriptase-polymerase chain reaction.Results: Progesterone receptor protein was first detected at gestational day 12 in the urethral plate and mesenchyma. At later stages staining intensity increased with a greater progesteron...
Martin J Cohn - One of the best experts on this subject based on the ideXlab platform.
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single cell transcriptomic analysis of external Genitalia reveals complex and sexually dimorphic cell populations in the early Genital Tubercle
Developmental Biology, 2021Co-Authors: Brooke A Armfield, Martin J CohnAbstract:Abstract External Genital organs are among the most recognizable sexually dimorphic characters. The penis and clitoris develop from the embryonic Genital Tubercle, an outgrowth at the anterior margin of the cloaca that undergoes an extensive period of development in male and female embryos prior to the onset of sexual differentiation. In mice, differentiation into the penis and clitoris begins around embryonic day (E)15.5. Current knowledge of cell types that comprise the Genital Tubercle is limited to a few studies that have fate mapped derivatives of endoderm, mesoderm, and ectoderm. Here we use single cell transcriptomics to characterize the cell populations in the Genital Tubercles of male and female mouse embryos at E14.5, approximately 24 h before the onset of sexual differentiation, and we present the first comprehensive atlas of single-cell gene expression during external Genital development. Clustering analyses and annotation using marker genes shows 19 distinct cell populations in E14.5 Genital Tubercles. Mapping of cell clusters to anatomical locations using in situ gene expression patterns revealed granularity of cellular specializations and positional identities. Although E14.5 precedes sexually dimorphic morphogenesis of the Genital Tubercle, comparative analysis of males and females identified sexual dimorphisms at the single cell level, including male-specific cell clusters with transcriptional signatures of smooth muscle and bone progenitors, both of which are known to be sexually dimorphic in adult Genitalia, as well as immune cells. These results provide a new resource for classification of external Genital cell types based on gene expression profiles and reveal sex-specific cellular specializations in the early Genital Tubercle.
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foxa1 and foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with shh
Developmental Biology, 2020Co-Authors: Marissa L Gredler, Ashley W. Seifert, Sara E Patterson, Martin J CohnAbstract:ConGenital anomalies of external Genitalia affect approximately 1 in 125 live male births. Development of the Genital Tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the Genital Tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, Genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.
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ARTICLE
2016Co-Authors: Ashley W. Seifert, Zhengui Zheng, I K. Ormerod, Martin J CohnAbstract:During embryonic development, cells are instructed which position to occupy, they interpret these cues as differentiation programmes, and expand these patterns by growth. Sonic hedgehog (Shh) specifi es positional identity in many organs; however, its role in growth is not well understood. In this study, we show that inactivation of Shh in external Genitalia extends the cell cycle from 8.5 to 14.4 h, and Genital growth is reduced by ~ 75 %. Transient Shh signalling establishes pattern in the Genital Tubercle; however, transcriptional levels of G1 cell cycle regulators are reduced. Consequently, G1 length is extended, leading to fewer progenitor cells entering S-phase. Cell cycle genes responded similarly to Shh inactivation in Genitalia and limbs, suggesting that Shh may regulate growth by similar mechanisms in different organ systems. The fi nding that Shh regulates cell number by controlling the length of specifi c cell cycle phases identifi es a novel mechanism by which Shh elaborates pattern during appendage development
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development of the cloaca hemipenes and hemiclitores in the green anole anolis carolinensis
Sexual Development, 2014Co-Authors: Marissa L Gredler, Thomas J Sanger, Martin J CohnAbstract:In most amniotes, the intromittent organ is a single phallus; however, squamates (lizards, snakes, and amphisbaenians) have paired hemiphalluses. All amniotes studied to date initiate external Genital development with the formation of paired Genital swellings. In mammals, archosaurs, and turtles, these swellings merge to form a single Genital Tubercle, the precursor of the penis and clitoris; however, in squamates, the paired Genital buds remain separate, giving rise to the hemiphalluses (hemipenes in males and hemiclitores in females). Although the molecular genetics and sexual differentiation of the Genital Tubercle have been investigated in mammals and birds, little is known about hemiphallus development. Here we describe development of the cloaca and hemiphallus in the green anole, Anolis carolinensis. Each hemiphallus originates as a protuberance that emerges at the ventral base of the hindlimb bud. Development of the hemipenes resembles penis development; however, differences exist in their tissue composition, morphogenesis, and gene expression patterns. These findings reveal aspects of phallus development that appear to be evolutionarily labile, both within squamates and more broadly among reptiles, and identify features that are conserved across amniotes. Our results, together with parallel studies in other reptilian taxa, suggest potential mechanisms for the diversification of external Genital form.
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Developmental basis of phallus reduction during bird evolution.
Current Biology, 2013Co-Authors: Ana M. Herrera, Simone G. Shuster, Claire L. Perriton, Martin J CohnAbstract:Summary Background One of the most puzzling events in evolution is the reduction and loss of the phallus in birds. All birds reproduce by internal fertilization, but only ∼3% of birds have retained a phallus capable of intromission. A number of hypotheses have been proposed for the evolutionary mechanisms that drove phallus reduction; however, the underlying developmental mechanisms are unknown. Results We investigated Genital development in two sister clades of birds, Galliformes (land fowl), most of which lack an intromittent phallus, and Anseriformes (waterfowl), which have well developed phalluses; and in two outgroups, Paleognathae (emus) and Crocodilia (alligators). Galliform embryos undergo cryptic development of a Genital Tubercle, the precursor of the phallus, but this later undergoes apoptosis, leading to regression of the Tubercle. At the molecular level, a derived pattern of Bmp4 expression was identified in chick (a galliform) Genital Tubercles. Inhibition of Bmp signaling in chick Genitalia rescues cells from apoptosis and prevents phallus regression, whereas activation of Bmp signaling in duck (an anseriform) Genitalia induces a galliform-like pattern of apoptosis. Thus, distal Bmp activity is necessary and sufficient to induce apoptosis in Galloanserae Genital Tubercles. Conclusions Our results indicate that evolutionary reduction of the intromittent phallus in galliform birds occurred not by disruption of outgrowth signals but by de novo activation of cell death by Bmp4 in the Genital Tubercle. These findings, together with discoveries implicating Bmps in evolution of beak shape, feathers, and toothlessness, suggest that modulation of Bmp gene regulation played a major role in the evolution of avian morphology. Video Abstract
Kentaro Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Bmp4 is an essential growth factor for the initiation of Genital Tubercle (GT) outgrowth.
Congenital anomalies, 2019Co-Authors: Daiki Kajioka, Kentaro Suzuki, Shoko Matsushita, Naomi Nakagata, Shoko Nakada, Shinichi Miyagawa, Toru Takeo, YamadaAbstract:The external Genitalia are appendage organs outgrowing from the posterior body trunk. Murine Genital Tubercle (GT), anlage of external Genitalia, initiates its outgrowth from embryonic day (E) 10.5 as a bud structure. Several growth factors such as fibroblast growth factor (FGF), Wnt and Sonic hedgehog (Shh) are essential for the GT outgrowth. However, the mechanisms of initiation of GT outgrowth are poorly understood. We previously identified bone morphogenetic protein (Bmp) signaling as a negative regulator for GT outgrowth. We show here novel aspects of Bmp4 functions for GT outgrowth. We identified the Bmp4 was already expressed in cloaca region at E9.5, before GT outgrowth. To analyze the function of Bmp4 at early stage for the initiation of GT outgrowth, we utilized the Hoxa3-Cre driver and Bmp4 flox/flox mouse lines. Hoxa3 Cre/+ ; Bmp4 flox/flox mutant mice showed the hypoplasia of GT with reduced expression of outgrowth promoting genes such as Wnt5a, Hoxd13 and p63, whereas Shh expression was not affected. Formation of distal urethral epithelium (DUE) marked by the Fgf8 expression is essential for controlling mesenchymal genes expression in GT and subsequent its outgrowth. Furthermore, Fgf8 expression was dramatically reduced in such mutant mice indicating the defective DUE formation. Hence, current results indicate that Bmp4 is an essential growth factor for the initiation of GT outgrowth independent of Shh signaling. Thus, Bmp4 positively regulates for the formation of DUE. The current study provides new insights into the function of Bmp signaling at early stage for the initiation of GT outgrowth.
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androgen regulates mafb expression through its 3 utr during mouse urethral masculinization
Endocrinology, 2016Co-Authors: Shoko Matsushita, Shinjiro Hino, Mikita Suyama, Yukiko Ogino, Kentaro Suzuki, Tetsuya Sato, Takahiro Matsumoto, Akiko Omori, Satoshi Inoue, Gen YamadaAbstract:External Genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the Genital Tubercle, which is the anlage of external Genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3′ untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3′UTR. Androgen receptor is bound to such AREs in 3′UTR during urethral masculinization. In addition to 3′UTR, Mafb 5′UTR also showed androgen responsiveness. Moreover, we also demonstrated that β-catenin, one of Genital Tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insigh...
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Retinoic Acid Signaling Regulates Sonic Hedgehog and Bone Morphogenetic Protein Signalings During Genital Tubercle Development
Birth Defects Research Part B-developmental and Reproductive Toxicology, 2011Co-Authors: Kentaro Suzuki, Kenichiro Mihara, Kenta Yashiro, Yukiko Ogino, Hiroshi Hamada, Daisuke Matsumaru, Naomi Nakagata, Sylvia M EvansAbstract:Retinoic acid (RA) plays pivotal roles in organogenesis, and both excessive and reduced amounts of RA cause developmental abnormalities. Reproductive organs are susceptible to teratogen toxigenicity, and the Genital Tubercle (GT) is one such representative organ. The physiological function of endogenous RA signaling and the mechanisms of RA-induced teratogenicity are poorly understood during the GT development. The objective of this study is to understand the developmental and teratogenic roles of RA during GT development by analyzing genetically modified mouse models. We found dynamic patterns of gene expression for the RA-synthesizing enzyme, Raldh2, and for the RA-catabolizing enzyme, Cyp26b1, during GT development. Rarb, an indicator gene for RA signaling, starts its expression in the prospective corpus cavernosum penis and in the urethral plate epithelium (UE), which plays central roles during GT development. Excessive RA signaling in Cyp26b1 ! /! mutants leads to abnormal extents of cell proliferation and differentiation during GT development, and also upregulates expression of growth factor signalings. They include Sonic hedgehog (Shh) signaling and Bone morphogenetic protein (Bmp) signaling, which are expressed in the UE and its bilateral mesenchyme. RA signaling positively regulatesShh and Bmp4 expression during GT development as testified also by the experiment of RA administration and analyses of loss‐of-function of RA signaling mutants. Thus, RA signaling is involved in the developmental cascade necessary for UE formation and GT development. Birth Defects Res (Part B) 95:79‐88, 2012. r2011 Wiley Periodicals, Inc.
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retinoic acid signaling regulates sonic hedgehog and bone morphogenetic protein signalings during Genital Tubercle development
Birth Defects Research Part B-developmental and Reproductive Toxicology, 2011Co-Authors: Liqing Liu, Kenichiro Mihara, Kenta Yashiro, Yukiko Ogino, Kentaro Suzuki, Hiroshi Hamada, Daisuke Matsumaru, Naomi Nakagata, Zhonghua Liu, Sylvia M EvansAbstract:Retinoic acid (RA) plays pivotal roles in organogenesis, and both excessive and reduced amounts of RA cause developmental abnormalities. Reproductive organs are susceptible to teratogen toxigenicity, and the Genital Tubercle (GT) is one such representative organ. The physiological function of endogenous RA signaling and the mechanisms of RA-induced teratogenicity are poorly understood during the GT development. The objective of this study is to understand the developmental and teratogenic roles of RA during GT development by analyzing genetically modified mouse models. We found dynamic patterns of gene expression for the RA-synthesizing enzyme, Raldh2, and for the RA-catabolizing enzyme, Cyp26b1, during GT development. Rarb, an indicator gene for RA signaling, starts its expression in the prospective corpus cavernosum penis and in the urethral plate epithelium (UE), which plays central roles during GT development. Excessive RA signaling in Cyp26b1(-/-) mutants leads to abnormal extents of cell proliferation and differentiation during GT development, and also upregulates expression of growth factor signalings. They include Sonic hedgehog (Shh) signaling and Bone morphogenetic protein (Bmp) signaling, which are expressed in the UE and its bilateral mesenchyme. RA signaling positively regulatesShh and Bmp4 expression during GT development as testified also by the experiment of RA administration and analyses of loss-of-function of RA signaling mutants. Thus, RA signaling is involved in the developmental cascade necessary for UE formation and GT development.
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molecular genetic cascades for external Genitalia formation an emerging organogenesis program
Developmental Dynamics, 2006Co-Authors: Gen Yamada, Kentaro Suzuki, Naomi Nakagata, Shinichi Miyagawa, Ryuma Haraguchi, Yoshihiko Satoh, M Kamimura, H Kataoka, Atsushi Kuroiwa, Yiping ChenAbstract:External Genitalia are anatomical structures located at the posterior embryonic region as part of several uroGenital/reproductive organs. The embryonic anlage of the external Genitalia, the Genital Tubercle (GT) develops as a bud-shaped structure with an initial urethral plate and later urethra. Embryonic external Genitalia are considered to be one of the appendages. Recent experiments suggest that essential regulatory genes possess similar functions for the outgrowth regulation of the GT and limb appendages. The transient embryonic epithelia located in the distal GT are called the distal urethral epithelium (DUE) regulating, at least in part, the (distal) GT development. This review covers the available data about early patterning of GT and discusses the molecular developmental similarities and points of divergence between the different appendages. Development of the male and female external Genitalia is also reviewed.
Gerald R Cunha - One of the best experts on this subject based on the ideXlab platform.
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development of the human penis and clitoris
Differentiation, 2018Co-Authors: Laurence S. Baskin, Adriane Sinclair, Dylan Isaacson, Maya Overland, Joel Shen, Yi Li, Gerald R CunhaAbstract:Abstract The human penis and clitoris develop from the ambisexual Genital Tubercle. To compare and contrast the development of human penis and clitoris, we used macroscopic photography, optical projection tomography, light sheet microscopy, scanning electron microscopy, histology and immunohistochemistry. The human Genital Tubercle differentiates into a penis under the influence of androgens forming a tubular urethra that develops by canalization of the urethral plate to form a wide diamond-shaped urethral groove (opening zipper) whose edges (urethral folds) fuse in the midline (closing zipper). In contrast, in females, without the influence of androgens, the vestibular plate (homologue of the urethral plate) undergoes canalization to form a wide vestibular groove whose edges (vestibular folds) remain unfused, ultimately forming the labia minora defining the vaginal vestibule. The neurovascular anatomy is similar in both the developing human penis and clitoris and is the key to successful surgical reconstructions.
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morphology of mouse external Genitalia implications for a role of estrogen in sexual dimorphism of the mouse Genital Tubercle
The Journal of Urology, 2010Co-Authors: Jennifer H Yang, Gerald R Cunha, Julia Menshenina, Ned J Place, Laurence S. BaskinAbstract:Purpose: We examined the role of androgens and estrogens in mammalian sexual differentiation by morphological characterization of adult wt and mutant mouse external Genitalia. We tested the hypothesis that external Genitalia development depends on androgen and estrogen action.Materials and Methods: We studied serial sections of the external Genitalia of the CD-1 and C57BL6 wt strains of adult mice (Charles River Laboratories, Wilmington, Massachusetts). We recorded linear measurements of key structures in each specimen, including the urethra, erectile tissue, bone and cartilage. We used similar methodology to analyze mice mutant for estrogen receptor α (αERKO) and androgen receptor (XTfm/Y) (Jackson Laboratory, Bar Harbor, Maine).Results: Morphology in XTfm/Y adult murine external Genitalia was remarkably similar to that in wt females. Bone and clitoral length was similar in wt females and XTfm/Y mice. Conversely the αERKO clitoris was 59% longer and bone length in αERKO females was many-fold longer than ...
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induction of hypospadias in a murine model by maternal exposure to synthetic estrogens
Environmental Research, 2004Co-Authors: Carlos R. Torres, Kamakshi Raimondo, Selcuk Yucel, Gerald R Cunha, Laurence S. BaskinAbstract:Abstract We tested the hypothesis that maternal exposure to synthetic estrogen can cause hypospadias in male offspring and defined the morphological changes in the disrupted urethral seam. Timed pregnant C57/6 mice were exposed to synthetic estrogens. The Genital Tubercles were examined for the presence of hypospadias using histology, three-dimensional computer reconstruction, and plastic cast injection molds of the urethra. Microscopic serial analysis confirmed the presence of hypospadias, which occurred in ∼50% of the synthetic-estrogen-treated male fetuses. No effect was seen in the female embryos. Plastic cast injection showed that affected males had a shorter total urethral length and loss of male anatomic features such as the prostatic utricle. Exposure to synthetic estrogens during pregnancy affects the normal development of the urethra in the mouse. We conclude that endocrine disrupters play an important role in Genital Tubercle anomalies.
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Anatomical Studies of the Fibroblast Growth Factor-10 Mutant, Sonic Hedge Hog Mutant and Androgen Receptor Mutant Mouse Genital Tubercle
Advances in experimental medicine and biology, 2004Co-Authors: Selcuk Yucel, Gerald R Cunha, Wenhui Liu, Dwight Cordero, Anne Donjacour, Laurence S. BaskinAbstract:ConGenital Genital abnormalities have a diverse spectrum from hypospadias to cloacal anomalies. The molecular events in the normal and abnormal development of the Genital Tubercle (GT) are still obscure. Genetically engineered mice with specific gene deletions that affect Genital anatomy are a useful tool to better understand the etiology of Genital abnormalities. In this study, we compared the Genital Tubercle anatomy of the androgen receptor (AR) deficient, fibroblastic growth factor (FGF)-10 deficient and Sonic HedgeHog (Shh) deficient mutant male mice to that of the wild type male and female mouse.
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Epithelial-mesenchymal interactions in development of the mouse fetal Genital Tubercle.
Cells tissues organs, 1999Co-Authors: Eric A. Kurzrock, Laurence S. Baskin, Gerald R CunhaAbstract:Epithelial-mesenchymal interactions play a central role in the development of uroGenital organs. We hypothesized that normal development of the external Genitalia depends upon proper mesenchymal-epithelial signaling. The mesenchyme of the adult mouse penis consists of a corpus cavernosum and proximal and distal bones. The differentiation of penile mesenchyme into bone and cartilage begins after birth and can be accelerated by androgens. After determining the sex, Genital Tubercles of fetal mice at gestational day 15 were removed. The Genital Tubercles were trypsinized and microdissected to remove the epidermis and urethra from the mesenchyme. Recombinant specimens were created by combining Genital Tubercle mesenchyme with Genital Tubercle epithelium, bladder epithelium or tail epidermis. Tissues were grafted under the renal capsule of male athymic mice. After 3 weeks of growth, grafts were removed from the kidney, weighed and stained with hematoxylin and eosin, Alcian blue and peanut agglutinin. Male and female grafts showed no difference in growth or differentiation. Intact grafts and recombinant grafts, irrespective of the epithelial source, grew significantly more than grafts of the mesenchyme only. Recombinant grafts demonstrated a significantly higher prevalence of cartilage formation and mesenchymal differentiation compared to grafts of the mesenchyme without epithelium. Since heterologous epithelium is able to induce equivalent growth and differentiation of phallic mesenchyme, epithelium carries a permissive, but critical, role in Genital mesenchyme development.
Gen Yamada - One of the best experts on this subject based on the ideXlab platform.
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5α dihydrotestosterone negatively regulates cell proliferation of the periurethral ventral mesenchyme during urethral tube formation in the murine male Genital Tubercle
Journal of Andrology, 2017Co-Authors: H Suzuki, Shoko Matsushita, K Suzuki, Gen YamadaAbstract:Summary Androgen is an essential factor involved in masculinization of external Genitalia. Failure of the exposure to 5α-dihydrotestosterone (DHT) causes a hypoplastic penile size and urethral abnormality. The main pathology of hypospadias is defective urethral closure on the ventral side of the penis. Hormone-dependent genes are suggested as the causative factors. However, the detailed mechanisms of DHT functions on urethral tube formation remain unknown. Androgen is both a positive and negative regulator of cell proliferation. The roles of locally converted DHT in cell proliferation at the periurethral mesenchyme have not been elucidated. We revealed the expression pattern of 5α-reductase type 2 mRNA (Srd5a2) and local DHT distribution by direct measurement in this study. We also analyzed periurethral mesenchymal cell proliferation status using systematic three-dimensional (3D) reconstruction analyses. A prominent Srd5a2 expression and localized DHT distribution on the ventral side of the Genital Tubercle were detected. Cell proliferation was reduced in this mesenchymal region during urethral formation. The current results suggest the presence of the possible negative regulation of cell proliferation by DHT. Moreover, cell proliferation related to urethral tube formation was revealed to be DHT dose dependent. These data are expected to contribute to the understanding of the mode of regulation of cell proliferation related to urethral tube formation by DHT. These findings may also offer insight into the understanding of human hypospadias and related hormone-dependent factors.
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androgen regulates mafb expression through its 3 utr during mouse urethral masculinization
Endocrinology, 2016Co-Authors: Shoko Matsushita, Shinjiro Hino, Mikita Suyama, Yukiko Ogino, Kentaro Suzuki, Tetsuya Sato, Takahiro Matsumoto, Akiko Omori, Satoshi Inoue, Gen YamadaAbstract:External Genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the Genital Tubercle, which is the anlage of external Genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3′ untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3′UTR. Androgen receptor is bound to such AREs in 3′UTR during urethral masculinization. In addition to 3′UTR, Mafb 5′UTR also showed androgen responsiveness. Moreover, we also demonstrated that β-catenin, one of Genital Tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insigh...
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molecular genetic cascades for external Genitalia formation an emerging organogenesis program
Developmental Dynamics, 2006Co-Authors: Gen Yamada, Kentaro Suzuki, Naomi Nakagata, Shinichi Miyagawa, Ryuma Haraguchi, Yoshihiko Satoh, M Kamimura, H Kataoka, Atsushi Kuroiwa, Yiping ChenAbstract:External Genitalia are anatomical structures located at the posterior embryonic region as part of several uroGenital/reproductive organs. The embryonic anlage of the external Genitalia, the Genital Tubercle (GT) develops as a bud-shaped structure with an initial urethral plate and later urethra. Embryonic external Genitalia are considered to be one of the appendages. Recent experiments suggest that essential regulatory genes possess similar functions for the outgrowth regulation of the GT and limb appendages. The transient embryonic epithelia located in the distal GT are called the distal urethral epithelium (DUE) regulating, at least in part, the (distal) GT development. This review covers the available data about early patterning of GT and discusses the molecular developmental similarities and points of divergence between the different appendages. Development of the male and female external Genitalia is also reviewed.
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Regulation of external Genitalia development by concerted actions of FGF ligands and FGF receptors
Anatomy and Embryology, 2004Co-Authors: Yoshihiko Satoh, Ryuma Haraguchi, Tracy J. Wright, Suzanne L. Mansour, Juha Partanen, Mohammad K. Hajihosseini, Veraragavan P. Eswarakumar, Peter Lonai, Gen YamadaAbstract:Members of the fibroblast growth factor (FGF) family play diverse roles during the development and patterning of various organs. In human and mice, 22 FGFs and four receptors derived from several splice variants are present. Redundant expression and function of FGF genes in organogenesis have been reported, but their roles in embryonic external Genitalia, Genital Tubercle (GT), development have not been studied in detail. To address the role of FGF during external Genitalia development, we have analyzed the expression of FGF genes ( Fgf8 , 9 , 10 ) and receptor genes ( Fgfr1 , r2IIIb , r2IIIc ) in GT of mice. Furthermore, Fgf10 and Fgfr2IIIb mutant mice were analyzed to elucidate their roles in embryonic external Genitalia development. Fgfr2IIIb was expressed in urethral plate epithelium during GT development. Fgfr2IIIb mutant mice display urethral dysmorphogenesis. Marker gene analysis for urethral plate and bilateral mesenchymal formation suggests the existence of epithelial-mesenchymal interaction during urethral morphogenesis. Therefore, FGF10/FGFR2IIIb signals seem to constitute a developmental cascade for such morphogenesis.