Gen Yamada

Wakayama Med U/ Kumamoto/Kurume/ kagoshima/MPI Fassberg Goettingen EU/Osaka

Purpose The pathophysiology of penis extends to erectile dysfunction (ED) to conditions including sexually transmitted diseases (STDs) and cancer. To date, there has been little research evaluating vascular drainage from the penis. We aimed to evaluate penile blood flow in vivo and analyze its possible relationship with the lymphatic maker. Materi...

IGLL5 is shown to be located near super-enhancer (SE) in B-cell tumors, and this gene is frequently mutated and a target of translocation in B-cell tumors. These results suggest roles of the IGLL5 in tumorigenesis; however, its functional properties have been unclear. We found that two mature B-cell lymphoma cell lines expressed IGLL5 mRNA with Cλ1...

Background Lymphedema is an intractable disease that can be caused by injury to lymphatic vessels, such as by surgical treatments for cancer. It can lead to impaired joint mobility in the extremities and reduced quality of life. Chronic inflammation due to infiltration of various immune cells in an area of lymphedema is thought to lead to local fib...

Background The corpus cavernosum (CC) containing sinusoids plays fundamental roles for erection. Analysis of pathological changes in the erectile system is studied by recent experimental systems. Various in vitro models utilizing genital mesenchymal‐derived cells and explant culture systems are summarized. Methods 3D reconstruction of section imag...

The post-surgical fluid leakage from the tubular tissues is a critical symptom after gastrointestinal or urinary tract surgeries. Elucidating the mechanism for such abnormalities is vital in surgical and medical science. The exposure of the fluid such as peritonitis due to urinary or gastrointestinal perforation has been reported to induce severe i...

Teleost fishes exhibit complex sexual characteristics in response to androgens, such as fin enlargement and courtship display. However, the molecular mechanisms underlying their evolutionary acquisition remain largely unknown. To address this question, we analyse medaka (Oryzias latipes) mutants deficient in teleost-specific androgen receptor ohnol...

Embryonic external genitalia [genital tubercle (GT)] protrude from the cloaca and outgrow as cloacal development progresses. Individual gene functions and knockout phenotypes in GT development have been extensively analyzed; however, the interactions between these genes are not fully understood. In this study, we investigated the role of p63, focus...

Transient Receptor Potential (TRP) ion channels mediate the influx of cations into cells responding to chemical or physical stimuli. TRP vanilloid 1 (TRPV1) regulates cutaneous functions. Its function in cutaneous wound healing, however, has not been clarified. The current study elucidated the role of TRPV1 in cutaneous wound healing of dorsal circ...

While androgen is considered a pivotal regulator of sexually dimorphic development, it remains unclear how it orchestrates the differentiation of reproductive organs. Using external genitalia development as a model, we showed that androgen, through the transcription factor MafB, induced cell migration by remodeling the local extracellular matrix (E...

Erection is an essential process which requires the male penis for copulation. This copulatory process depends on the vascular dynamic regulation of the penis. The corpus cavernosum (CC) in the upper (dorsal) part of the penis plays a major role in regulating blood flow inside the penis. When the CC is filled with blood, the sinusoids, including mi...

Wound healing is an important process in various diseases, and elucidating the underlying mechanism is essential for developing therapeutic strategies. We investigated whether the loss of transient receptor potential ankyrin 1 (TRPA1) affects the cutaneous wound healing process in mice. We assessed the formation of granulation tissue by myofibrobla...

Many industrial chemicals have been reported as anti-androgenic substances. Exposure to these substances represents a potential risk to human health, particularly to the development of reproductive organs such as embryonic external genitalia (eExG). Currently, there is a need for more assay systems that can elucidate the toxicological actions and m...

Teleost fishes exhibit complex unique sexual characteristics, such as fin enlargement and courtship display, in response to androgens. However, the molecular mechanisms underlying their evolutionary acquisition remain largely unknown. To address this question, we analysed medaka ( Oryzias latipes ) mutants deficient in androgen receptor ohnologs (...

Purpose: Penile research is expected to reveal new targets for treatment and prevention of the complex mechanisms of its disorder including erectile dysfunction (ED). Thus, analyses of the molecular processes of penile ED and continuous erection as priapism are essential issues of reproductive medicine. Methods: By performing mouse N-ethyl-N-nit...

Background:. Surgery for zygomatic complex fractures primarily aims to obtain facial symmetry. We investigated facial symmetry specific to lower eyelid bulges following zygomatic complex fractures approached through the lower eyelid. Methods:. Forty-one consecutive patients underwent treatment of zygomatic complex fractures by swinging eyelid appro...

The development of embryonic external genitalia (eExG) into characteristic male structures, such as urethra and penile erectile tissues, depends on 5α-dihydrotestosterone (DHT). Although the corpus cavernosum (CC) is well known as essential for erectile function in adults, its developmental process and its dependency on DHT have been unknown. To re...

The murine penile erectile tissues including corpus cavernosum (CC) are composed of blood vessels, smooth muscle, and connective tissue, showing marked sexual differences. It has been known that the androgens are required for sexually dimorphic organogenesis. It is however unknown about the features of androgen signaling during mouse CC development...

In the newborn, penile length is determined by a number of androgen dependent and independent factors. The current literature suggests that there are inter-racial differences in stretched penile length in the newborn and although congenital micropenis should be defined as a stretched penile length of less than 2.5SDS of the mean for the correspondi...

Background Because of the high frequency of chronic edema formation in the current “aged” society, analyses and detailed observation of post-surgical edema are getting more required. Post-surgical examination of the dynamic vasculature including L.V. (Lymphatic Vasculature) to monitor edema formation has not been efficiently performed. Hence, proce...

External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling has been linked to Robinow’s syndro...

Significance Androgen plays essential roles for sex differentiation of external genitalia through regulating male-biased genes. Even females can differentiate into male-type external genitalia depending on the degree of androgenic exposure. However, the mechanisms underlying androgen responsiveness in females are poorly defined. Here, we demonstrat...

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and t...

Purpose Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three‐dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the...

Male penis is required to become erect during copulation. In the upper (dorsal) part of penis, the erectile tissue termed corpus cavernosum (CC) plays fundamental roles for erection by regulating the inner blood flow. When blood flows into the CC, the microvascular complex termed sinusoidal space is reported to expand during erection. A novel in vi...

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital pr...

Visualization of the surgically operated tissues is vital to improve surgical model animals including mouse. Urological surgeries for urethra include series of fine manipulations to treat the increasing number of birth defects such as hypospadias. Hence visualization of the urethral status is vital. Inappropriate urethral surgical procedure often l...

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus co...

Background/aim: The mouse vagina exhibits stratified squamous epithelium, which is comprised of multiple cell layers. We previously showed that erbB signaling, induced by epithelial estrogen receptor 1 (ESR1), is required for the initial differentiation of the epithelium. However, the downstream effector that mediates terminal differentiation in t...

Development of external genitalia (ExG) has been a topic of long mystery in the field of organogenesis research. Early stage male and female of mouse embryos develop a common genital tubercle (GT) in the perineum whose outgrowth extends distally from the posterior cloacal regions. Concomitant with GT outgrowth, the cloaca is divided into urogenital...

The morphogenesis of mammalian embryonic external genitalia (eExG) shows dynamic differences between males and females. In genotypic males, eExG are masculinized in response to androgen signaling. Disruption of this process can give rise to multiple male reproductive organ defects. Currently, mechanisms of androgen-driven sexually dimorphic organog...

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. Howe...

Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower (caudal) end of endoderm. Such endodermal epithelia and surrounding mesenchyme interact with various signals to form the external genitalia. External genitalia (the anlage termed as genita...

Gene duplication is a dominant driving force of evolution. The steroid hormone receptor (SR) gene family is thought to have arisen from gene duplication. However, the molecular events which produce new protein functions after genome duplication have not been fully understood. Teleost fishes present an excellent model to investigate an accurate evol...

Purpose: We evaluated the association of hypospadias with 17 susceptibility loci previously identified by a European genome-wide association study (GWAS) in Japanese patients. We also examined the expression of candidate genes in male mouse embryos to discuss the possible underlying mechanisms of this disease. Materials and methods: We enrolled...

Sex steroid hormones including estrogens and androgens play fundamental roles in regulating reproductive activities and they act through estrogen and androgen receptors (ESR and AR). These steroid receptors have evolved from a common ancestor in association with several gene duplications. In most vertebrates, this has resulted in two ESR subtypes (...

The biology of masculinization is fundamentally important for understanding the embryonic developmental processes that are involved in the development of the male reproductive tract, external genitalia, and also the tumorigenesis of prostate cancer. The molecular mechanisms of masculinization are of interest to many researchers and clinicians invol...

Impaired androgen activity induces defective sexual differentiation of the male reproductive tract, including hypospadias, an abnormal formation of the penile urethra. Androgen signaling in the urethral mesenchyme cells (UMCs) plays essential roles in driving dimorphic urethral development. However, cellular events for sexual differentiation remain...

Control experiments for X-gal staining analysis. (a, b) Sections of X-gal staining of adult uterus at 6 weeks of age in Rosa-LacZ mice. Endometrial stroma is negative for X-gal staining. Non-specific weak X-gal signal is observed in the luminal side of the endometrial epithelium and the gland. (b) shows higher magnification views of the red box in...

Expression patterns of Wnt signaling components in the mesonephric region and embryonic uterus. (a) LEF1 is expressed in the coelomic epithelium and mesenchyme at E11.0. (b, c) At E12.5 and E15.5, LEF1 expression is observed in the müllerian duct (MD) epithelium and its surrounding mesenchymal cells. LEF1 immunohistochemistry (IHC) signal is weakly...

Expression pattern of estrogen receptor α (ERα) in the mesonephric region and embryonic uterus. (a) ERα expression is not detected in the coelomic epithelium and mesenchyme at E11.0. At E12.5 and E15.5, ERα expression is observed in the mesonephric region (b) and mesenchymal cells surrounding the müllerian duct (c). (a–c) Müllerian and wolffian duc...

In mammals, the müllerian duct (MD) is an embryonic tubular structure that gives rise to the female reproductive tract (FRT). The MD originates from the coelomic epithelium (CoE) and takes on a rostral to caudal shape to establish the primary structure of the FRT under the regulation of morphogenetic signals. During these developmental processes, t...

Estrogens play fundamental roles in regulating reproductive activities and they act through estrogen receptor (ESR) in all vertebrates. Most vertebrates have two ESR subtypes (ESR1 and ESR2), whereas teleost fish have at least three (Esr1, Esr2a and Esr2b). Intricate functionalization has been suggested among the Esr subtypes, but to date, distinct...

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 mark...

Reciprocal epithelial-mesenchymal interactions and several signalling pathways regulate the development of the genital tubercle (GT), an embryonic primordium of external genitalia. The morphology of the adult male external genitalia of the Asian house musk shrew Suncus murinus (hereafter, laboratory name: suncus) belonging to the order Eulipotyphla...

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...

The abnormalities in the urogenital organs are frequently observed as human developmental diseases. Among such diseases, the defects in the upper part of external genitalia are rather rare named epispadias. The cleft in the dorsal part of external genitalia often reaches to the urethra. In general, the urogenital abnormalities accompany defects in...

Murine reproductive tissues of the external genitalia and perineum develop with remarkably distinctive characteristics in males and females. Although many researches on such mouse organ development have been reported, there are still limited parameters that evaluate the developmental sexual differences of external genitalia and perineum. Furthermor...

External genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the genital tubercle (GT), 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 regulato...

Sexual dimorphism in mouse reproductive tissues is observable in adult, post-natal, and embryonic stages. The development of sexually dimorphic tissues starts with an ambisexual structure. It is followed by sex-specific organogenesis as guided by different signaling pathways that occur from late embryonic stages. The measurement of the anogenital d...

External genitalia is the essential organ showing hormone-dependent sexual differentiation. Its morphology is Quite different between male and female. Androgen signaling is an essential factor for the masculinization of genital tubercle (GT), the anlage of external genitalia Our previous results provide evidences that Mafb is a strong candidate gen...

Steroid hormone receptor family provides an example of evolution of diverse transcription factors through whole genome duplication (WGD). However, little is known about how their functions have been evolved after the duplication. Teleosts present a good model to investigate an accurate evolutionary history of protein function after WGD, because a t...

The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the urorectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, increased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal...

The division of the embryonic cloaca is the most essential event for the formation of digestive and urinary tracts. The defective development of the cloaca results in anorectal malformations (ARMs; 2-5 per 10,000 live births). However, the developmental and pathogenic mechanisms of ARMs are unclear. In the current study, we visualized the epithelia...

Purpose: To examine the developmental pathobiology of the eyelid and the cornea caused by epithelial β-catenin gain-of-function (gof) during mouse embryogenesis. Methods: Compound mutant mice (Ctnnb1(GOFOSE) , gof of β-catenin in the epidermis and the ocular surface epithelium) were generated by time-mating keratin 5-promoter-Cre recombinase (Kr...

The developmental processes of the genital tubercle (GT), the anlage of the external genitalia, possess several developmental aspects, including GT outgrowth, urethral tube formation, and epithelial differentiation of the urethra. The GT comprises the mesenchyme derived from the lateral mesoderm, ectodermal epithelium, and endodermal epithelium (em...

The Wolffian duct (WD) is a primordium of the male reproductive tract and kidney collecting duct system. Fibroblast growth factor receptors (FGFRs), members of the receptor tyrosine kinase (RTK) family, are essential for kidney development. Although the functions of FGFR signaling in kidney morphogenesis have been analyzed, their function in WD dev...

Significance Androgen is essential for the masculinization of external genitalia such as the organ size and the male-type urethra in mammals. However, the genes downstream of androgen, which are responsible for these masculinization processes, have not been identified. Here, we show v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( M...

Sexual differentiation is a tightly regulated series of events which transform the indifferent gonads and genitalia into sex-specific structures. This is driven by hormones produced by the fetal testes, primarily testosterone (T). However, masculinization of each structure does not occur synchronously and, until recently, it was presumed that andro...

One of the main functions of androgen is in the sexually dimorphic development of the male reproductive tissues. During embryogenesis, androgen determines the morphogenesis of male specific organs, such as the epididymis, seminal vesicle, prostate and penis. Despite the critical function of androgens in masculinization, the downstream molecular mec...

The BC (bulbocavernosus) is a sexually dimorphic muscle observed only in males. ARKO (Androgen receptor knock out) 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 du...

Prostate is a male sex accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particular...

Numerous studies support a role of phosphatase and tensin homolog deleted from chromosome 10 (Pten) as a tumor suppressor gene that controls epithelial cell homeostasis to prevent tumor formation. Mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing hom...

The cloaca is temporally formed and eventually divided by the urorectal septum (URS) during urogenital and anorectal organ development. Although congenital malformations, such as anorectal malformations (ARMs), are frequently observed during this process, the underlying pathogenic mechanisms remain unclear. β-Catenin is a critical component of cano...

In mammalian urorectal development, the urorectal septum (urs) descends from the ventral body wall to the cloaca membrane (cm) to partition the cloaca into urogenital sinus and rectum. Defective urs growth results in human congenital anorectal malformations (ARMs), and their pathogenic mechanisms are unclear. Recent studies only focused on the impo...

The study of the external genitalia is divided into 2 developmental stages: the formation and growth of a bipotential genital tubercle (GT) and the sexual differentiation of the male and female GT. The sexually dimorphic processes, which occur during the second part of GT differentiation, are suggested to be governed by androgen signaling and more...

During organogenesis, Sonic hedgehog (Shh) possesses dual functions: Shh emanating from midline structures regulates the positioning of bilateral structures at early stages, whereas organ-specific Shh locally regulates organ morphogenesis at later stages. The mesonephros is a transient embryonic kidney in amniote, whereas it becomes definitive adul...

Background/aims: Missense, nonsense, and splice mutations in the Fibroblast Growth Factor 8(FGF8) have recently been identified in patients with hypothalamo-pituitary dysfunction and craniofacial anomalies. Here, we report a male patient with a frameshift mutation in FGF8. Case report: The patient exhibited micropenis, craniofacial anomalies, an...

Androgens play key roles in the morphological specification of male type sex attractive and reproductive organs, while little is known about the developmental mechanisms of such secondary sex characters. Medaka offers a clue about sexual differentiation. They show a prominent masculine sexual character for appendage development, the formation of pa...

Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4(Lst)) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the devel...

β-catenin is a molecule belonging to the armadillo family of proteins that is a crucial core-component of cellular adherens junctions, and a component of the canonical Wnt-signaling pathway. We attempted to analyze the functional significance of ectodermal-derived β-catenin during the development of the mouse genital tubercle, a mammalian anlage of...

Details of cosmid clones and PCR products. A. Size of cosmid inserts and PCR products. The cosmid C3, shown in red, contains the ETn. B. DNA electrophoresis (Not I digestion) to measure the size of the cosmid clone inserts. The insert of cosmid clone C3 (shown in red) was bigger than the expected size based on its end-sequence tags and wild-type ge...

Establishment of neomycin-resistant (neo) mice. A. Wild-type (WT) and neo alleles. Cleavage at Sph I sites was used to distinguish between the two alleles. The blue and red bars indicate a fragment detected by Southern blotting for the WT allele and neo allele, respectively. The probe is shown as a black box. Primer pairs (5′Sd-S1/3′Sd-A1 and 5′Sd-...

Establishment of ETn-Gm13336/Ptf1aneo mice. A. Upper panel: PCR-based detection of the ETn. Lower panel: PCR-based detection of the neo allele. Both the ETn and neo were transmitted to the offspring, suggesting that the ETn and Gm13336-Ptf1aneo are on the same chromosome. B. Hematoxylin and eosin staining of pancreases in E18.5 embryos showed no pa...

Ectopic expression of Ptf1a and downregulation of Cdx2 and its downstream targets. A. Quantitative RT-PCR analyses of the expression of Ptf1a, Cdx2, T, Wnt3a, and Cyp26a1 in the E10.0 embryos of WT, Ptf1a/+, and Ptf1a/Ptf1a littermates. Upregulation of Ptf1a and downregulation of Cdx2 and T, but not of Wnt3a and Cyp26a1 were observed. The data repr...

Supplementary Materials and Methods. Cosmid library of Sd homozygotes, DNA sequencing, Extraction and reverse transcription of RNA, Cloning of the Gm13336 cDNA, Skeletal preparations, X-ray computed tomography, Establishment of an Sd/+ ES cell line, Construction of replacement vectors for CAG-Gm13336 and CAG-mGm13336, and establishment of Ayu21-B13...

Establishment of Sd/+ ES cell clones. A. Genotyping of ES cell lines. ES cell lines were established from blastocysts obtained from a mating between an Sd/+ heterozygote and a wild-type mouse. In this figure, four lines were positive for the ETn allele and three of the four were positive for Sry, meaning that three were male Sd/+ ES cell lines. B....