In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has been proposed to represent an inappropriate reactivation of an embryonic differentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. Here we show that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age. This epithelial hyperplasia and dysplasia also occurs in heterozygous mice, indicating haploinsufficiency for this phenotype. Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and that loss of a single allele may predispose to prostate carcinogenesis. The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis.
More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Estradiol-17 (E 2 ) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether E 2 elicits epithelial mitogenesis through epithelial ER versus indirectly via ERpositive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB͞c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and͞or stroma (S), or lacking ER altogether: wt-S ؉ wt-E, wt-S ؉ ko-E, ko-S ؉ ko-E, and ko-S ؉ wt-E. Tissue recombinants were grown for 4 weeks as subrenal capsule grafts in intact female nude mice, then the hosts were treated with either E 2 or oil a week after ovariectomy. Epithelial labeling index and ER expression were determined by [ 3 H]thymidine autoradiography and immunohistochemistry, respectively. In tissue recombinants containing wt-S (wt-S ؉ wt-E, wt-S ؉ ko-E), E 2 induced a similar large increase in epithelial labeling index compared with oil-treated controls in both types of tissue recombinants despite the absence of epithelial ER in wt-S ؉ ko-E tissue recombinants. This proliferative effect was blocked by an ER antagonist, indicating it was mediated through ER. In contrast, in tissue recombinants prepared with ko-S (ko-S ؉ ko-E and ko-S ؉ wt-E), epithelial labeling index was low and not stimulated by E 2 despite epithelial ER expression in ko-S ؉ wt-E grafts. In conclusion, these data demonstrate that epithelial ER is neither necessary nor sufficient for E 2 -induced uterine epithelial proliferation. Instead, E 2 induction of epithelial proliferation appears to be a paracrine event mediated by ER-positive stroma. These data in the uterus and similar studies in the prostate suggest that epithelial mitogenesis in both estrogen and androgen target organs are stromally mediated events.
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.
In combination with androgens, estrogens can induce aberrant growth and malignancy of the prostate gland. Estrogen action is mediated through two receptor subtypes: estrogen receptors alpha (ERalpha) and beta (ERbeta). Wild-type (wt) and transgenic mice lacking a functional ERalpha (alphaERKO) or ERbeta (betaERKO) were treated with the synthetic estrogen diethylstilbestrol (DES). DES induced prostatic squamous metaplasia (SQM) in wt and betaERKO but not in alphaERKO mice, indicating an essential role for ERalpha, but not ERbeta, in the induction of SQM of prostatic epithelium. In order to determine the respective roles of epithelial and stromal ERalpha in this response, the following tissue recombinants were constructed with prostatic epithelia (E) and stroma (S) from wt and ERKO mice: wt-S+wt-E, alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E. A metaplastic response to DES was observed in wt-S+wt-E tissue recombinants. This response to DES involved multilayering of basal epithelial cells, expression of cytokeratin 10, and up-regulation of the progesterone receptor. Tissue recombinants containing alphaERKO-E and/or -S (alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E) failed to respond to DES. Therefore, full and uniform epithelial SQM requires ERalpha in the epithelium and stroma. These results provide a novel insight into the cell-cell interactions mediating estrogen action in the prostate via ERalpha.
Hereditary peripheral neuropathies are the most common monogenetically inherited diseases of the nervous system. The prevalence of the Hereditary Motor and Sensory Neuropathy Type 1A (HMSN 1A or Charcot-Marie-Tooth Neuropathy 1A, CMT1A) alone is estimated to be as high as 1/5000. In 1991, a duplication on chromosome 17p11.2 was identified as the causative genetic defect of CMT1A. Since then causative mutations in 17 genes have been identified. This review summarises the clinical and molecular genetic features of primary inherited neuropathies. It is aimed primarily at clinicians and geneticists. Therefore less emphasis is placed on the pathology and the (often unknown) underlying biological disease mechanisms.
The distribution of androgen receptors (AR) in developing male BALB/c mouse reproductive organs was determined by 3H-dihydrotestosterone steroid autoradiography. The efferent ductules, urogenital sinus (UGS) and Wolffian ducts, and their derivatives, the epididymis, ductus deferens, seminal vesicles, coagulating glands, prostate and bulbouretheral glands, were examined in mice from 13-days fetal (gestation = 19-20 days) to 10 days postnatal. All organs contained AR in their mesenchymal/stromal cells at all times examined. The Wolffian ducts and UGS did not contain epithelial AR on days 13-14 or 16 of gestation. The efferent ductule was the first site of epithelial AR expression in the male tract during development; this organ had epithelial AR on day 16 and at all subsequent times. The epididymis and ductus deferens contained epithelial AR beginning on day 19 of gestation. Seminal vesicle and coagulating gland epithelium was AR- at birth, became weakly AR+ on day 1, and was strongly AR+ on day 2 and subsequently. Prostatic epithelium was AR- up to day 4, when some positive epithelial cells were seen; the prostatic epithelium was strongly AR+ on day 6 and subsequently. The last organ to begin expressing epithelial AR was the bulbouretheral gland; this epithelium did not become clearly AR+ until day 8 postnatally. In summary, these results indicate that initial epithelial AR expression in the male reproductive tract occurs in a clear temporal sequence and proceeds in a cranial-caudal direction. Epithelial AR first appear in the efferent ductules, followed by initial epithelial AR expression in Wolffian-derived organs and finally in the UGS-derived organs. The factors controlling initial epithelial AR expression are unclear, but mesenchyme may be involved.
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