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Gary D. Hammer - One of the best experts on this subject based on the ideXlab platform.
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Adrenocortical Function, Factors Controlling Development Thereof
Encyclopedia of Stress, 2007Co-Authors: Tobias Else, Gary D. HammerAbstract:The adrenal gland, like the gonad and the kidney, is derived from components of the Urogenital Ridge. Adrenocortical development is directed by a tight program of sequential expression and activation of transcription factor genes. The interplay of these factors directs the morphological development as well as the functional programming of the adrenal gland as the end organ of the hypothalamic-pituitary-adrenocortical stress axis. To date, the network of SF1 and DAX1 is the most well-characterized system in adrenocortical development.
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Genetic analysis of adrenal absence: agenesis and aplasia
Trends in endocrinology and metabolism: TEM, 2005Co-Authors: Tobias Else, Gary D. HammerAbstract:The adrenal cortex shares a common embryological heritage with the gonad and kidney: all are derived from components of the Urogenital Ridge. Adrenocortical specification from this embryonic structure and the ultimate organogenesis of the adrenal gland are directed by the sequential expression of transcriptional regulators, with later development being additionally mediated by endocrine hormones that regulate organ maintenance and tissue differentiation. Recent advancements in the field of human and mouse genetics have accumulated evidence for a host of novel factors involved in these processes, such as the hedgehog signaling network and peptides derived from proopiomelanocortin.
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Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator
Human molecular genetics, 2004Co-Authors: Catherine E. Keegan, Tobias Else, Janna Hutz, Maja Adamska, Sonalee P. Shah, Amy E. Kent, John M. Howes, Wesley G. Beamer, Gary D. HammerAbstract:Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the Urogenital Ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. We report the identification of a splice donor mutation in a novel gene, which is the mouse ortholog of a newly discovered telomeric regulator. This gene (Acd) has recently been characterized as a novel component of the TRF1 protein complex that controls telomere elongation by telomerase. Characterization of Acd transcripts in mutant animals reveals two abnormal transcripts, consistent with a splicing defect. Expression of a wild-type Acd transgene in acd mutants rescues the observed phenotype. Most mutants die within 1-2 days of life on the original genetic background. Analysis of these mutant embryos reveals variable, yet striking defects in caudal specification, limb patterning and axial skeleton formation. In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 is expanded in the dorsal-ventral axis of the apical ectodermal Ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos shows abnormal vertebral fusions in cervical, lumbar and caudal regions. This is the first report to show that a telomeric regulator is required for proper Urogenital Ridge differentiation, axial skeleton specification and limb patterning in mice.
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The Adrenocortical Dysplasia (acd) Mouse: Mutation in a Novel Gene Causes a Pleiotropic Phenotype of Urogenital Defects and Caudal Dysgenesis
Endocrine Research, 2004Co-Authors: Catherine E. Keegan, Tobias Else, Janna Hutz, Maja Adamska, Sonalee P. Shah, Amy E. Kent, John M. Howes, Wesley G. Beamer, Gary D. HammerAbstract:The adrenocortical dysplasia (DW/J‐acd/J) mouse is a spontaneous autosomal recessive mutant with developmental defects in organs derived from the Urogenital Ridge: the kidneys, gonads, and adrenals. Adrenocortical dysplasia and hypofunction are predominant features in surviving adult mice. Adult female mutant mice exhibit subnormal fertility secondary to an overall decrease in folliculogenesis in the ovary, and males are completely infertile due to germ cell degeneration in the testes. Fifty percent of adult acd mutant mice develop hydronephrosis due to ureteral hyperplasia. On the original genetic background, most mutants die within 1–2 days of life. Analysis of acd mutant embryos on this genetic background reveals variable, yet striking defects in caudal specification, limb patterning, and axial skeletal formation. We have identified a splice donor site mutation in a novel gene (Acd) in acd mutant mice. Characterization of Acd transcripts produced in acd mutant tissues reveals two abnormal transcripts a...
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convergence of wnt signaling and steroidogenic factor 1 sf 1 on transcription of the rat inhibin α gene
Journal of Biological Chemistry, 2003Co-Authors: Brian M. Gummow, Jonathon N. Winnay, Gary D. HammerAbstract:Abstract The action of a variety of peptide hormones is critical for proper growth and differentiation of the Urogenital Ridge, which ultimately gives rise to the kidney, adrenal cortex, and gonad. One such class of peptides is the Wnt family of secreted glycoproteins that is classically involved in development of cell polarity and cell fate determination. Notably, alterations in Wnt-4 expression in mice and humans result in profound defects in Urogenital Ridge development, including dysregulation of kidney, gonadal, and adrenal growth. The nuclear receptor steroidogenic factor-1 (SF-1) has been implicated as a downstream effector of peptide hormone signaling during Urogenital Ridge development as evidenced by both the activation of SF-1-dependent transcription in the adrenal cortex by signaling molecules such as protein kinase A and by the adrenal and gonadal agenesis in mice with null mutations in SF-1. We hypothesized that Wnt-dependent signaling cascades regulate SF-1-dependent transcription of genes required for adreno-gonadal development. Specifically, the data demonstrate that β-catenin synergizes with SF-1 to activate the α-inhibin promoter through formation of a transcriptional complex. The activation requires an intact SF-1 RE and is independent of TCF/Lef. These data support the recent observation that β-catenin can participate in nuclear receptor-mediated transcriptional activation and extend the findings to the monomer binding class of orphan nuclear receptors.
Patricia K Donahoe - One of the best experts on this subject based on the ideXlab platform.
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an albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant c terminal mullerian inhibiting substance
Technology (Elmsford N.Y.), 2013Co-Authors: David Pepin, Mien V Hoang, Fotini Nicolaou, Katherine Hendren, Leo Benedict, Ahmad Almoujahed, Amanda Sosulski, Anna Marmalidou, Demetrios G Vavvas, Patricia K DonahoeAbstract:Mullerian Inhibiting Substance (MIS) has been shown to inhibit ovarian cancer cells both in-vitro and in-vivo. Furthermore, recent evidence suggests that MIS may effectively target a putative ovarian cancer progenitor cell population enriched by a panel of CD44+, CD24+, Ep-CAM+, and E-cadherin-cell surface markers. In order to accommodate clinical testing of MIS in ovarian cancer patients, the production of recombinant human MIS must be optimized to increase yield and purity. Here we show that, compared to wild type, the substitution of the MIS leader sequence to that of human serum albumin, combined with a modification of the endogenous cleavage site from RAQR/S to a furin/kex2 RARR/S consensus site results in high expression, increased C-terminus cleavage and a reduction in unwanted cryptic internal cleavage products when produced in CHO cells. Purified MIS containing these alterations retains its capacity to induce regression of the Mullerian duct in fetal rat embryonic Urogenital Ridge assays.
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Müllerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells early in Müllerian duct regression
Development (Cambridge England), 2006Co-Authors: Yong Zhan, David T. Maclaughlin, Thomas F. Manganaro, Jose Teixeira, Akihiro Fujino, Paul P. Szotek, Nelson A. Arango, Patricia K DonahoeAbstract:Examination of Mullerian inhibiting substance (MIS) signaling in the rat in vivo and in vitro revealed novel developmental stage- and tissue-specific events that contributed to a window of MIS responsiveness in Mullerian duct regression. The MIS type II receptor (MISRII)-expressing cells are initially present in the coelomic epithelium of both male and female Urogenital Ridges, and then migrate into the mesenchyme surrounding the male Mullerian duct under the influence of MIS. Expression of the genes encoding MIS type I receptors, Alk2 and Alk3 , is also spatiotemporally controlled; Alk2 expression appears earlier and increases predominantly in the coelomic epithelium, whereas Alk3 expression appears later and is restricted to the mesenchyme, suggesting sequential roles in Mullerian duct regression. MIS induces expression of Alk2 , Alk3 and Smad8 , but downregulates Smad5 in the Urogenital Ridge. Alk2 -specific small interfering RNA (siRNA) blocks both the transition of MISRII expression from the coelomic epithelium to the mesenchyme and Mullerian duct regression in organ culture. Mullerian duct regression can also be inhibited or accelerated by siRNA targeting Smad8 and Smad5 , respectively. Thus, the early action of MIS is to initiate an epithelial-to-mesenchymal transition of MISRII-expressing cells and to specify the components of the receptor/SMAD signaling pathway by differentially regulating their expression.
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mullerian inhibiting substance regulates androgen synthesis at the transcriptional level
Endocrinology, 1999Co-Authors: Jose Teixeira, Eric Fynnthompson, Anita H Payne, Patricia K DonahoeAbstract:Mullerian-inhibiting substance (MIS) is a hormone produced by Sertoli cells of the fetal testes that causes regression of the Mullerian ducts, the precursors to female reproductive tract structures that are present in the bipotential Urogenital Ridge. MIS is also produced in the adult gonads of both males and females, albeit at much lower levels than those measured during the fetal and perinatal periods. Adult transgenic mice chronically overexpressing MIS exhibit severe gonadal abnormalities and, in males, dramatically reduced levels of testosterone, which might lead to the incomplete virilization observed in some of the males. To understand the roles played by MIS in the adult gonad, we performed Northern analyses to show that the MIS type II receptor is expressed in purified Leydig cells and in two rodent Leydig cell lines, R2C and MA-10. Addition of purified recombinant human MIS to cultures of both R2C and MA-10 cells reduced steroid production. With MA-10 cells, the reduction of testosterone secreti...
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Developmental expression of a candidate mullerian inhibiting substance type II receptor
Endocrinology, 1996Co-Authors: Jose Teixeira, David T. Maclaughlin, Elizabeth A. Catlin, Mary M. Lee, Paresh C. Shah, Nobuyuki Morikawa, Peter L. Hudson, John F. Wing, Patricia K DonahoeAbstract:We have isolated a candidate Mullerian inhibiting substance (MIS) type II receptor complementary DNA from an embryonic rat Urogenital Ridge library and have studied its binding to MIS, its developmental pattern of expression and tissue distribution. By in situ hybridization with a full-length riboprobe, the receptor is expressed in the mesenchymal cells surrounding the Mullerian duct at embryonic days 14, 15, and 16 and in tubular and follicular structures of the rat fetal gonads. Expression of the messenger RNA was also seen in the granules cells and seminiferous tubules of pubertal gonads. Northern analysis revealed that the MIS type II receptor messenger RNA is highly expressed in embryonic, pubertal, and adult testes and ovaries, as well as in the gravid uterus. The timing of expression in the gonads of both sexes was also analyzed by Northern analyses that showed high levels of expression at the time of Mullerian duct regression, much lower levels neonatally and prepubertally and then increased expre...
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developmental expression of four novel serine threonine kinase receptors homologous to the activin transforming growth factor β type ii receptor family
Developmental Dynamics, 1993Co-Authors: Wei Wu He, Seichii Hirobe, Michael L. Gustafson, Patricia K DonahoeAbstract:Serine/threonine kinase transmembrane proteins are a new family of growth factor signal transducers that includes several isoforms of the activin type II receptor and the type II receptor for transforming growth factor-β. In an effort to clone the receptor for Mullerian inhibiting substance, a member of the transforming growth factor-β superfamily, oligonucleotide primers designed from conserved regions of these receptors' kinase domains were used for PCR amplification of fetal rat Urogenital Ridge cDNA. We isolated four novel receptors in this manner (desingnated R1–R4), each of which has structural features of the previously cloned kinases, including a small extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and an intracellular serine/threonine kinase domain. In addition, each has characteristic kinase subdomains and conserved serine/threonine kinase sequences found in this family. Northern analysis revealed mRNA expression of R1-R4 in several tissues, including fetal Urogenital Ridge, testis, and ovary, as well as brain and lung. In situ hybridization further localized R1 to mesenchyme of the 14.5 to 15-day fetal rat Mullerian duct and to oocytes of preantral and antral follicles, sites that are consistent with the predicted localization of Mullerian inhibiting substance receptor. In addition, R2 localized specifically to seminiferous tubules of the postnatal testis. These newest members of the activin and transforming growth factor-β type II receptor family should help define the molecular mechanisms by which this ligand superfamily affects cell growth and differentiation via membrane phosphorylation. © 1993 wiley-Liss, Inc.
Pedro Acién - One of the best experts on this subject based on the ideXlab platform.
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Blind hemibladder, ectopic ureterocele, or Gartner’s duct cyst in a woman with Müllerian malformation and supposed unilateral renal agenesis: a case report
International Urogynecology Journal, 2010Co-Authors: Pedro Acién, Maribel Acien, Jesús Romero-marotoAbstract:Genital anomalies associated with unilateral renal agenesis are generally due to agenesis or hypoplasia of the entire Urogenital Ridge or distal mesonephric aberrations. However, renal adysplasia could also occur in association with anomalies of the ventral Urogenital sinus. The patient presented didelphys uterus in the superior uterine segment, a septate cervix, and a simple vagina. After transvaginal puncture and injection of a contrast agent into the bulge observed in the right vaginal wall, a filled sac or cavity was detected, possibly a hemibladder. This structure continued upward with a possible dilated tortuous ureter that filled retrogradely. Magnetic resonance imaging also showed the presence of the right blind paravaginal sac. Right hemitrigone and ureteral orifice were absent in the cystourethroscopy. No right kidney was found, despite the use of multiple imaging techniques. Blind hemibladder, ectopic ureterocele, and Gartner’s duct cyst seem to be a possible diagnosis associated to Müllerian malformations and supposed unilateral renal agenesis. Therefore, Müllerian anomalies without combined mesonephric alteration could be associated with conditions of the ventral Urogenital sinus, including blind hemibladder or ectopic ureterocele with secondary renal dysplasia.
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blind hemibladder ectopic ureterocele or gartner s duct cyst in a woman with mullerian malformation and supposed unilateral renal agenesis a case report
International Urogynecology Journal, 2010Co-Authors: Pedro Acién, Maribel Acien, Jesus RomeromarotoAbstract:Genital anomalies associated with unilateral renal agenesis are generally due to agenesis or hypoplasia of the entire Urogenital Ridge or distal mesonephric aberrations. However, renal adysplasia could also occur in association with anomalies of the ventral Urogenital sinus. The patient presented didelphys uterus in the superior uterine segment, a septate cervix, and a simple vagina. After transvaginal puncture and injection of a contrast agent into the bulge observed in the right vaginal wall, a filled sac or cavity was detected, possibly a hemibladder. This structure continued upward with a possible dilated tortuous ureter that filled retrogradely. Magnetic resonance imaging also showed the presence of the right blind paravaginal sac. Right hemitrigone and ureteral orifice were absent in the cystourethroscopy. No right kidney was found, despite the use of multiple imaging techniques. Blind hemibladder, ectopic ureterocele, and Gartner’s duct cyst seem to be a possible diagnosis associated to Mullerian malformations and supposed unilateral renal agenesis. Therefore, Mullerian anomalies without combined mesonephric alteration could be associated with conditions of the ventral Urogenital sinus, including blind hemibladder or ectopic ureterocele with secondary renal dysplasia.
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Renal agenesis in association with malformation of the female genital tract
American Journal of Obstetrics and Gynecology, 1991Co-Authors: Pedro Acién, José A. Ruiz, José F. Hernandez, Francisco Susarte, Angel Martin Del MoralAbstract:Four cases of renal agenesis with an ipsilateral blind vagina and two cases with agenesis of all organs derived from one Urogenital Ridge are presented. These cases confirm the association of renal agenesis with these genital malformations and support the hypothesis that the embryologic development of the vagina is derived from the fused mesonephric ducts.
Jesus Romeromaroto - One of the best experts on this subject based on the ideXlab platform.
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blind hemibladder ectopic ureterocele or gartner s duct cyst in a woman with mullerian malformation and supposed unilateral renal agenesis a case report
International Urogynecology Journal, 2010Co-Authors: Pedro Acién, Maribel Acien, Jesus RomeromarotoAbstract:Genital anomalies associated with unilateral renal agenesis are generally due to agenesis or hypoplasia of the entire Urogenital Ridge or distal mesonephric aberrations. However, renal adysplasia could also occur in association with anomalies of the ventral Urogenital sinus. The patient presented didelphys uterus in the superior uterine segment, a septate cervix, and a simple vagina. After transvaginal puncture and injection of a contrast agent into the bulge observed in the right vaginal wall, a filled sac or cavity was detected, possibly a hemibladder. This structure continued upward with a possible dilated tortuous ureter that filled retrogradely. Magnetic resonance imaging also showed the presence of the right blind paravaginal sac. Right hemitrigone and ureteral orifice were absent in the cystourethroscopy. No right kidney was found, despite the use of multiple imaging techniques. Blind hemibladder, ectopic ureterocele, and Gartner’s duct cyst seem to be a possible diagnosis associated to Mullerian malformations and supposed unilateral renal agenesis. Therefore, Mullerian anomalies without combined mesonephric alteration could be associated with conditions of the ventral Urogenital sinus, including blind hemibladder or ectopic ureterocele with secondary renal dysplasia.
Jesús Romero-maroto - One of the best experts on this subject based on the ideXlab platform.
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Blind hemibladder, ectopic ureterocele, or Gartner’s duct cyst in a woman with Müllerian malformation and supposed unilateral renal agenesis: a case report
International Urogynecology Journal, 2010Co-Authors: Pedro Acién, Maribel Acien, Jesús Romero-marotoAbstract:Genital anomalies associated with unilateral renal agenesis are generally due to agenesis or hypoplasia of the entire Urogenital Ridge or distal mesonephric aberrations. However, renal adysplasia could also occur in association with anomalies of the ventral Urogenital sinus. The patient presented didelphys uterus in the superior uterine segment, a septate cervix, and a simple vagina. After transvaginal puncture and injection of a contrast agent into the bulge observed in the right vaginal wall, a filled sac or cavity was detected, possibly a hemibladder. This structure continued upward with a possible dilated tortuous ureter that filled retrogradely. Magnetic resonance imaging also showed the presence of the right blind paravaginal sac. Right hemitrigone and ureteral orifice were absent in the cystourethroscopy. No right kidney was found, despite the use of multiple imaging techniques. Blind hemibladder, ectopic ureterocele, and Gartner’s duct cyst seem to be a possible diagnosis associated to Müllerian malformations and supposed unilateral renal agenesis. Therefore, Müllerian anomalies without combined mesonephric alteration could be associated with conditions of the ventral Urogenital sinus, including blind hemibladder or ectopic ureterocele with secondary renal dysplasia.