scholarly journals The Wilms’ Tumor Suppressor Gene (wt1) Product Regulates Dax-1 Gene Expression during Gonadal Differentiation

1999 ◽  
Vol 19 (3) ◽  
pp. 2289-2299 ◽  
Author(s):  
Jungho Kim ◽  
Dirk Prawitt ◽  
Nabeel Bardeesy ◽  
Elena Torban ◽  
Caroline Vicaner ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Receptor Gene ◽  
Suppressor Gene ◽  
Gonadal Development ◽  
Early Event ◽  
Testicular Development ◽  
Gonadal Differentiation ◽  
Mobility Shift ◽  
Drash Syndrome

ABSTRACT Gonadal differentiation is dependent upon a molecular cascade responsible for ovarian or testicular development from the bipotential gonadal ridge. Genetic analysis has implicated a number of gene products essential for this process, which include Sry, WT1, SF-1, and DAX-1. We have sought to better define the role of WT1 in this process by identifying downstream targets of WT1 during normal gonadal development. We have noticed that in the developing murine gonadal ridge, wt1 expression precedes expression of Dax-1, a nuclear receptor gene. We document here that the spatial distribution profiles of both proteins in the developing gonad overlap. We also demonstrate that WT1 can activate the Dax-1 promoter. Footprinting analysis, transient transfections, promoter mutagenesis, and mobility shift assays suggest that WT1 regulates Dax-1via GC-rich binding sites found upstream of the Dax-1 TATA box. We show that two WT1-interacting proteins, the product of a Denys-Drash syndrome allele of wt1 and prostate apoptosis response-4 protein, inhibit WT1-mediated transactivation ofDax-1. In addition, we demonstrate that WT1 can activate the endogenous Dax-1 promoter. Our results indicate that the WT1–DAX-1 pathway is an early event in the process of mammalian sex determination.

scholarly journals Wilms' Tumor Protein Wt1 Is an Activator of the Anti-Müllerian Hormone Receptor Gene Amhr2

2007 ◽  
Vol 27 (12) ◽  
pp. 4355-4364 ◽  
Author(s):  
Jürgen Klattig ◽  
Ralph Sierig ◽  
Dagmar Kruspe ◽  
Birgit Besenbeck ◽  
Christoph Englert
Keyword(s):  
Wilms Tumor ◽  
Receptor Gene ◽  
Gonad Development ◽  
Essential Factor ◽  
Rare Form ◽  
Urogenital Development ◽  
Microarray Analyses ◽  
Drash Syndrome ◽  
Wt1 Protein

ABSTRACT The Wilms' tumor protein Wt1 plays an essential role in mammalian urogenital development. WT1 mutations in humans lead to a variety of disorders, including Wilms' tumor, a pediatric kidney cancer, as well as Frasier and Denys-Drash syndromes. Phenotypic anomalies in Denys-Drash syndrome include pseudohermaphroditism and sex reversal in extreme cases. We have used cDNA microarray analyses on Wt1 knockout mice to identify Wt1-dependent genes involved in sexual development. The gene most dramatically affected by Wt1 inactivation was Amhr2, encoding the anti-Müllerian hormone (Amh) receptor 2. Amhr2 is an essential factor for the regression of the Müllerian duct in males, and mutations in AMHR2 lead to the persistent Müllerian duct syndrome, a rare form of male pseudohermaphroditism. Here we show that Wt1 and Amhr2 are coexpressed during urogenital development and that the Wt1 protein binds to the promoter region of the Amhr2 gene. Inactivation and overexpression of Wt1 in cell lines was followed by immediate changes of Amhr2 expression. The identification of Amhr2 as a Wt1 target provides new insights into the role of Wt1 in sexual differentiation and indicates, in addition to its function in early gonad development and sex determination, a novel function for Wt1, namely, in Müllerian duct regression.

Role of the p16 tumor suppressor gene in cancer.

1998 ◽  
Vol 16 (3) ◽  
pp. 1197-1206 ◽  
Author(s):  
W H Liggett ◽  
D Sidransky
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Human Cancer ◽  
Suppressor Gene ◽  
Premalignant Lesions ◽  
Early Event ◽  
Cyclin Dependent Kinase ◽  
Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

A novel mutation of the WT1 gene (a tumor suppressor gene for Wilms' tumor) in a patient with Denys – Drash syndrome

1993 ◽  
Vol 2 (11) ◽  
pp. 1969-1970 ◽  
Author(s):  
Aklra Sakal ◽  
Kelko Tadokoro ◽  
Hiroko Yanagisawa ◽  
Shigeo Nagafuchi ◽  
Noriakl Hoshikawa ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Wilms Tumor ◽  
Novel Mutation ◽  
Suppressor Gene ◽  
Wt1 Gene ◽  
Drash Syndrome

scholarly journals Wt1 dictates the fate of fetal and adult Leydig cells during development in the mouse testis

2014 ◽  
Vol 307 (12) ◽  
pp. E1131-E1143 ◽  
Author(s):  
Qing Wen ◽  
Qiao-Song Zheng ◽  
Xi-Xia Li ◽  
Zhao-Yuan Hu ◽  
Fei Gao ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Testosterone Level ◽  
Leydig Cells ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Testicular Development ◽  
Gene Encoding ◽  
Testis Development ◽  
Adult Mice ◽  
Serum Lh

Wilms' tumor 1 ( Wt1) is a tumor suppressor gene encoding ∼24 zinc finger transcription factors. In the mammalian testis, Wt1 is expressed mostly by Sertoli cells (SCs) involved in testis development, spermatogenesis, and adult Leydig cell (ALC) steroidogenesis. Global knockout (KO) of Wt1 is lethal in mice due to defects in embryogenesis. Herein, we showed that Wt1 is involved in regulating fetal Leydig cell (FLC) degeneration and ALC differentiation during testicular development. Using Wt1−/flox; Amh-Cre mice that specifically deleted Wt1 in the SC vs. age-matched wild-type (WT) controls, FLC-like-clusters were found in Wt1-deficient testes that remained mitotically active from postnatal day 1 (P1) to P56, and no ALC was detected at these ages. Leydig cells in mutant adult testes displayed morphological features of FLC. Also, FLC-like cells in adult mutant testes had reduced expression in ALC-associated genes Ptgds, Sult1e1, Vcam1, Hsd11b1, Hsd3b6, and Hsd17b3 but high expression of FLC-associated genes Thbs2 and Hsd3b1. Whereas serum LH and testosterone level in mutant mice were not different from controls, intratesticular testosterone level was significantly reduced. Deletion of Wt1 gene also perturbed the expression of steroidogenic enzymes Star, P450c17, Hsd3b6, Hsd3b1, Hsd17b1, and Hsd17b3. FLCs in adult mutant testes failed to convert androstenedione to testosterone due to a lack of Hsd17b3, and this defect was rescued by coculturing with fetal SCs. In summary, FLC-like cells in mutant testes are putative FLCs that remain mitotically active in adult mice, illustrating that Wt1 dictates the fate of FLC and ALC during postnatal testis development.

WT1 and its disorders

2018 ◽  
Author(s):  
Nick Hastie ◽  
Eve Miller-Hodges
Keyword(s):  
Kidney Development ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Wilms Tumour ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Mesenchymal To Epithelial Transition ◽  
Children And Young Adults ◽  
Drash Syndrome

Mutations in the Wilms tumour suppressor gene, WT1, are associated with Wilms tumour in childhood. However, in addition WT1 has a key role in renal development, emerging roles in podocyte function, and a potential role in tissue regeneration. An understanding of WT1 is of increasing importance to clinical practice. WT1 is a complex gene with multiple isoforms. It is crucial for normal embryonic development, especially kidney development, where it is necessary for mesenchymal-to-epithelial transition to form the nephron. WT1 mutations lead to abnormalities in renal and genitourinary development, causing diseases such as Denys–Drash syndrome and Frasier syndrome as well as Wilms tumour. Recently, WT1 mutations have been recognized as a significant cause of isolated steroid-resistant nephrotic syndrome in children and young adults, without other associated syndromic features. WT1 continues to be expressed in adult podocytes, where it acts as a transcriptional activator of many podocyte genes. However, the specific role of WT1 in adult podocyte function remains poorly understood.

scholarly journals Painful ovulation in a 46,XX SRY −ve adult male with SOX9 duplication

2017 ◽  
Vol 2017 ◽  
Author(s):  
Nandini Shankara Narayana ◽  
Anne-Maree Kean ◽  
Lisa Ewans ◽  
Thomas Ohnesorg ◽  
Katie L Ayers ◽  
...  
Keyword(s):  
Major Gene ◽  
Hormone Replacement ◽  
Recurrence Risk ◽  
Gonadal Development ◽  
Testicular Development ◽  
List Type ◽  
Disorders Of Sexual Development ◽  
Region Duplication ◽  
Male Sex

Summary 46,XX disorders of sexual development (DSDs) occur rarely and result from disruptions of the genetic pathways underlying gonadal development and differentiation. We present a case of a young phenotypic male with 46,XX SRY-negative ovotesticular DSD resulting from a duplication upstream of SOX9 presenting with a painful testicular mass resulting from ovulation into an ovotestis. We present a literature review of ovulation in phenotypic men and discuss the role of SRY and SOX9 in testicular development, including the role of SOX9 upstream enhancer region duplication in female-to-male sex reversal. Learning points: In mammals, the early gonad is bipotent and can differentiate into either a testis or an ovary. SRY is the master switch in testis determination, responsible for differentiation of the bipotent gonad into testis. SRY activates SOX9 gene, SOX9 as a transcription factor is the second major gene involved in male sex determination. SOX9 drives the proliferation of Sertoli cells and activates AMH/MIS repressing the ovary. SOX9 is sufficient to induce testis formation and can substitute for SRY function. Assessing karyotype and then determination of the presence or absence of Mullerian structures are necessary serial investigations in any case of DSD, except for mixed gonadal dysgenesis identified by karyotype alone. Treatment is ideal in a multidisciplinary setting with considerations to genetic (implications to family and reproductive recurrence risk), psychological aspects (sensitive individualized counseling including patient gender identity and preference), endocrinological (hormone replacement), surgical (cosmetic, prophylactic gonadectomy) fertility preservation and reproductive opportunities and metabolic health (cardiovascular and bones).

scholarly journals Role of the Wilms' tumor suppressor gene Wt1 in pancreatic development

2018 ◽  
Vol 247 (7) ◽  
pp. 924-933 ◽  
Author(s):  
Laura Ariza ◽  
Ana Cañete ◽  
Anabel Rojas ◽  
Ramón Muñoz-Chápuli ◽  
Rita Carmona
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Pancreatic Development

Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome

Cell ◽  
1991 ◽  
Vol 67 (2) ◽  
pp. 437-447 ◽  
Author(s):  
Jerry Pelletier ◽  
Wendy Bruening ◽  
Clifford E. Kashtan ◽  
S. Michael Mauer ◽  
J. Carlos Manivel ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Wilms Tumor ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Urogenital Development ◽  
Drash Syndrome
Sign in / Sign up

Export Citation Format

Share Document