Talk:Prostate Development

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Cite this page: Hill, M.A. (2019, October 21) Embryology Prostate Development. Retrieved from



Development of the human prostate

Differentiation. 2018 Sep - Oct;103:24-45. doi: 10.1016/j.diff.2018.08.005. Epub 2018 Sep 4.

Cunha GR1, Vezina CM2, Isaacson D3, Ricke WA4, Timms BG5, Cao M3, Franco O6, Baskin LS3.

This paper provides a detailed compilation of human prostatic development that includes human fetal prostatic gross anatomy, histology, and ontogeny of selected epithelial and mesenchymal differentiation markers and signaling molecules throughout the stages of human prostatic development: (a) pre-bud urogenital sinus (UGS), (b) emergence of solid prostatic epithelial buds from urogenital sinus epithelium (UGE), (c) bud elongation and branching, (d) canalization of the solid epithelial cords, (e) differentiation of luminal and basal epithelial cells, and (f) secretory cytodifferentiation. Additionally, we describe the use of xenografts to assess the actions of androgens and estrogens on human fetal prostatic development. In this regard, we report a new model of de novo DHT-induction of prostatic development from xenografts of human fetal female urethras, which emphasizes the utility of the xenograft approach for investigation of initiation of human prostatic development. These studies raise the possibility of molecular mechanistic studies on human prostatic development through the use of tissue recombinants composed of mutant mouse UGM combined with human fetal prostatic epithelium. Our compilation of human prostatic developmental processes is likely to advance our understanding of the pathogenesis of benign prostatic hyperplasia and prostate cancer as the neoformation of ductal-acinar architecture during normal development is shared during the pathogenesis of benign prostatic hyperplasia and prostate cancer.

Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

PMID: 30224091

Maternal protein malnutrition: effects on prostate development and adult disease

J Dev Orig Health Dis. 2018 Mar 27:1-12. doi: 10.1017/S2040174418000168. [Epub ahead of print]

Rinaldi JC1, Santos SAA2, Colombelli KT2, Birch L3, Prins GS3, Justulin LA2, Felisbino SL2.


Well-controlled intrauterine development is an essential condition for many aspects of normal adult physiology and health. This process is disrupted by poor maternal nutrition status during pregnancy. Indeed, physiological adaptations occur in the fetus to ensure nutrient supply to the most vital organs at the expense of the others, leading to irreversible consequences in tissue formation and differentiation. Evidence indicates that maternal undernutrition in early life promotes changes in key hormones, such as glucocorticoids, growth hormones, insulin-like growth factors, estrogens and androgens, during fetal development. These alterations can directly or indirectly affect hormone release, hormone receptor expression/distribution, cellular function or tissue organization, and impair tissue growth, differentiation and maturation to exert profound long-term effects on the offspring. Within the male reproductive system, maternal protein malnutrition alters development, structure, and function of the gonads, testes and prostate gland. Consequently, these changes impair the reproductive capacity of the male offspring. Further, permanent alterations in the prostate gland occur at the molecular and cellular level and thereby affect the onset of late life diseases such as prostatitis, hyperplasia and even prostate cancer. This review assembles current thoughts on the concepts and mechanisms behind the developmental origins of health and disease as they relate to protein malnutrition, and highlights the effects of maternal protein malnutrition on rat prostate development and homeostasis. Such insights on developmental trajectories of adult-onset prostate disease may help provide a foundation for future studies in this field. KEYWORDS: androgen receptor; fetal programming; low-protein diet; prostatitis PMID: 29582717 DOI: 10.1017/S2040174418000168


Prostate organogenesis: tissue induction, hormonal regulation and cell type specification

Development. 2017 Apr 15;144(8):1382-1398. doi: 10.1242/dev.148270.

Toivanen R1, Shen MM2.

Abstract Prostate organogenesis is a complex process that is primarily mediated by the presence of androgens and subsequent mesenchyme-epithelial interactions. The investigation of prostate development is partly driven by its potential relevance to prostate cancer, in particular the apparent re-awakening of key developmental programs that occur during tumorigenesis. However, our current knowledge of the mechanisms that drive prostate organogenesis is far from complete. Here, we provide a comprehensive overview of prostate development, focusing on recent findings regarding sexual dimorphism, bud induction, branching morphogenesis and cellular differentiation. © 2017. Published by The Company of Biologists Ltd. KEYWORDS: Androgen signaling; Development; Differentiation; Induction; Prostate

PMID: 28400434 PMCID: PMC5399670 [Available on 2018-04-15] DOI: 10.1242/dev.148270

Female prostate: historical, developmental, and morphological perspectives

Cell Biol Int. 2017 Mar 4. doi: 10.1002/cbin.10759. [Epub ahead of print]

Biancardi MF1, Dos Santos FCA1, de Carvalho HF2, Sanches BDA2, Taboga SR3.


The female prostate was first described by Reijnier de Graaf in 1672, and even after several years this gland is still a matter of controversy. Part of this is because the biological function of this female gland is unclear. Moreover, when compared with the male prostate, the existence of this organ in females does not make sense, mainly when we consider that the major function of this gland is to produce a secretion that is responsible for guarantee the sperm survival and assure the reproductive success. However, even under a controversy field, we now have a lot of scientific information which enhances our knowledge of several important biological aspects of this gland. It is clear that this gland is found in some female mammals including humans, rodents, rabbits, bats, and dogs. Several studies with rodents showed that the female prostate is homolog of the male prostate, showing strong macroscopic and microscopic similarities with the ventral lobe of males. Besides these aspects, there are several studies reporting that diseases such as cysts, hyperplasia, and carcinoma may affect the female prostate. Therefore, although diseases involving the female prostate are rare, the susceptibility of this organ to develop lesions must be considered, especially in our recent years in which the exposure to endocrine-disrupting chemicals has greatly increased. Finally, further studies will be necessary to enhance our understanding about this gland, mainly of the developmental, evolutionary, and biological functions. © 2017 International Federation for Cell Biology.

KEYWORDS: development; female prostate; gerbil; prostatic lesions; testosterone

PMID 28258707 DOI: 10.1002/cbin.10759


Contribution of Caudal Müllerian Duct Mesenchyme to Prostate Development

Stem Cells Dev. 2016 Nov 15;25(22):1733-1741. Epub 2016 Oct 4.

Brechka H1, McAuley EM2, Lamperis SM3, Paner GP4, Vander Griend DJ1,3.


A fundamental understanding of prostate development and tissue homeostasis has the high potential to reveal mechanisms for prostate disease initiation and identify novel therapeutic approaches for disease prevention and treatment. Our current understanding of prostate lineage specification stems from the use of developmental model systems that rely upon the embryonic preprostatic urogenital sinus mesenchyme to induce the formation of mature prostate epithelial cells. It is unclear, however, how the urogenital sinus epithelium can derive both adult urethral glands and prostate epithelia. Furthermore, the vast disparity in disease initiation between these two glands highlights key developmental factors that predispose prostate epithelia to hyperplasia and cancer. In this study we demonstrate that the caudal Müllerian duct mesenchyme (CMDM) drives prostate epithelial differentiation and is a key determinant in cell lineage specification between urethral glands and prostate epithelia. Utilizing both human embryonic stem cells and mouse embryonic tissues, we document that the CMDM is capable of inducing the specification of androgen receptor, prostate-specific antigen, NKX3.1, and Hoxb13-positive prostate epithelial cells. These results help to explain key developmental differences between prostate and urethral gland differentiation, and implicate factors secreted by the caudal Müllerian duct as novel targets for prostate disease prevention and treatment. KEYWORDS: HOXB13; Müllerian duct; NKX3.1; androgen receptor; prostate

PMID 27595922 PMCID: PMC5105354 [Available on 2017-11-15] DOI: 10.1089/scd.2016.0088


Differential gene expression profiling of functionally and developmentally distinct human prostate epithelial populations

Prostate. 2015 May;75(7):764-76. doi: 10.1002/pros.22959. Epub 2015 Feb 7.

Liu H1, Cadaneanu RM, Lai K, Zhang B, Huo L, An DS, Li X, Lewis MS, Garraway IP.


BACKGROUND: Human fetal prostate buds appear in the 10th gestational week as solid cords, which branch and form lumens in response to androgen 1. Previous in vivo analysis of prostate epithelia isolated from benign prostatectomy specimens indicated that Epcam⁺ CD44⁻ CD49f(Hi) basal cells possess efficient tubule initiation capability relative to other subpopulations 2. Stromal interactions and branching morphogenesis displayed by adult tubule-initiating cells (TIC) are reminiscent of fetal prostate development. In the current study, we evaluated in vivo tubule initiation by human fetal prostate cells and determined expression profiles of fetal and adult epithelial subpopulations in an effort to identify pathways used by TIC. METHODS: Immunostaining and FACS analysis based on Epcam, CD44, and CD49f expression demonstrated the majority (99.9%) of fetal prostate epithelial cells (FC) were Epcam⁺ CD44⁻ with variable levels of CD49f expression. Fetal populations isolated via cell sorting were implanted into immunocompromised mice. Total RNA isolation from Epcam⁺ CD44⁻ CD49f(Hi) FC, adult Epcam⁺ CD44⁻ CD49f(Hi) TIC, Epcam⁺ CD44⁺ CD49f(Hi) basal cells (BC), and Epcam⁺ CD44⁻ CD49f(Lo) luminal cells (LC) was performed, followed by microarray analysis of 19 samples using the Affymetrix Gene Chip Human U133 Plus 2.0 Array. Data was analyzed using Partek Genomics Suite Version 6.4. Genes selected showed >2-fold difference in expression and P < 5.00E-2. Results were validated with RT-PCR. RESULTS: Grafts retrieved from Epcam⁺ CD44⁻ fetal cell implants displayed tubule formation with differentiation into basal and luminal compartments, while only stromal outgrowths were recovered from Epcam- fetal cell implants. Hierarchical clustering revealed four distinct groups determined by antigenic profile (TIC, BC, LC) and developmental stage (FC). TIC and BC displayed basal gene expression profiles, while LC expressed secretory genes. FC had a unique profile with the most similarities to adult TIC. Functional, network, and canonical pathway identification using Ingenuity Pathway Analysis Version 7.6 compiled genes with the highest differential expression (TIC relative to BC or LC). Many of these genes were found to be significantly associated with prostate tumorigenesis. CONCLUSIONS: Our results demonstrate clustering gene expression profiles of FC and adult TIC. Pathways associated with TIC are known to be deregulated in cancer, suggesting a cell-of-origin role for TIC versus re-emergence of pathways common to these cells in tumorigenesis. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. KEYWORDS: basal cell; fetal prostate; human prostate epithelial microarray; prostate stem cell; prostate tissue regeneration; prostate tubule initiation

PMID 25663004


The critical role of androgens in prostate development

Endocrinol Metab Clin North Am. 2011 Sep;40(3):577-90, ix.

Wilson JD. Source Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8857, USA.


Androgens are involved in every aspect of prostate development, growth, and function from early in male embryogenesis to prostatic hyperplasia in aging men and dogs. Likewise, androgen deprivation at any phase of life causes a decrease in prostate cell number and DNA content. The process by which the circulating androgen testosterone is converted to dihydrotestosterone in the tissue and dihydrotestosterone in turn gains access to the nucleus where it regulates gene expression, largely via interaction with a receptor protein, is understood, but the downstream control mechanisms by which hormonal signals are translated into differentiation, growth, and function are being unraveled. Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 21889722


The Effects of Aging on the Molecular and Cellular Composition of the Prostate Microenvironment


The role of Wnt5a in prostate gland development

Dev Biol. 2009 Apr 15;328(2):188-99. Epub 2009 Jan 14.

Huang L, Pu Y, Hu WY, Birch L, Luccio-Camelo D, Yamaguchi T, Prins GS.

Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60614, USA.


The Wnt genes encode a large family of secreted glycoproteins that play important roles in controlling tissue patterning, cell fate and proliferation during development. Currently, little is known regarding the role(s) of Wnt genes during prostate gland development. The present study examines the role of the noncanonical Wnt5a during prostate gland development in rat and murine models. In the rat prostate, Wnt5a mRNA is expressed by distal mesenchyme during the budding stage and localizes to periductal mesenchymal cells with an increasing proximal-to-distal gradient during branching morphogenesis. Wnt5a protein is secreted and localizes to periductal stroma, extracellular matrix and epithelial cells in the distal ducts. While Wnt5a expression is high during active morphogenesis in all prostate lobes, ventral prostate (VP) expression declines rapidly following morphogenesis while dorsal (DP) and lateral lobe (LP) expression remains high into adulthood. Steroids modulate prostatic Wnt5a expression during early development with testosterone suppressing Wnt5a and neonatal estrogen increasing expression. In vivo and ex vivo analyses of developing mouse and rat prostates were used to assess the functional roles of Wnt5a. Wnt5a(-/-) murine prostates rescued by organ culture exhibit disturbances in bud position and directed outgrowth leading to large bulbous sacs in place of elongating ducts. In contrast, epithelial cell proliferation, ductal elongation and branchpoint formation are suppressed in newborn rat prostates cultured with exogenous Wnt5a protein. While renal grafts of Wnt5a(-/-) murine prostates revealed that Wnt5a is not essential for cyto- and functional differentiation, a role in luminal cell polarity and lumenization of the ducts was indicated. Wnt5a suppresses prostatic Shh expression while Shh stimulates Wnt5a expression in a lobe-specific manner during early development indicating that Wnt5a participates in cross-talk with other members of the gene regulatory network that control prostate development. Although Wnt5a does not influence prostatic expression of other Wnt morphogens, it suppresses Wif-1 expression and can thus indirectly modulate Wnt signaling. In summary, the present finds demonstrate that Wnt5a is essential for normal prostate development where it regulates bud outgrowth, ductal elongation, branching, cell polarity and lumenization. These findings contribute to the growing body of knowledge on regulatory mechanisms involved in prostate gland development which are key to understanding abnormal growth processes associated with aging.

PMID 19389372 PMCID: PMC2828764

Imaging of the seminal vesicle and vas deferens

Radiographics. 2009 Jul-Aug;29(4):1105-21.

Kim B, Kawashima A, Ryu JA, Takahashi N, Hartman RP, King BF Jr.

Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Abstract The seminal vesicle (SV) and vas deferens (VD) are ancillary but essential urogenital organs. Understanding their embryologic features and anatomy can be helpful in evaluating various disorders of these organs. Recently, cross-sectional imaging modalities, including ultrasonography, computed tomography, and magnetic resonance (MR) imaging, have been increasingly used for evaluation of the SV and VD. The development of these organs is closely related to that of urinary organs, including the kidneys and ureters. Frequently, unilateral SV agenesis is associated with renal agenesis, and bilateral SV or VD agenesis is associated with mutations of the cystic fibrosis gene. Congenital SV cysts are commonly associated with ipsilateral renal agenesis or dysgenesis. These congenital anomalies can be well evaluated with MR imaging. Inflammation, post-radiation therapy changes, and amyloidosis of the SV appear as diffuse wall thickening and may mimic tumor invasion by prostate cancer. Primary neoplasms involving the SV and VD are extremely rare, whereas secondary neoplasms are much more common. Carcinoma from the prostate, bladder, or rectum can directly invade the SV and VD. Typical MR imaging findings of such invasion include a low-signal-intensity mass on T2-weighted images or soft-tissue thickening in the SV or VD along with loss of normal architecture.

Copyright RSNA, 2009

PMID 19605659

Morphologic variations of the prostatic utricle

Clin Anat. 2009 Apr;22(3):358-64.

Oh CS, Chung IH, Won HS, Kim JH, Nam KI.

Department of Anatomy, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea. Abstract Anatomical variations of the prostatic utricle (PU) have rarely been reported despite an understanding of them being required for diagnosing and treating PU anomalies. This study was performed on 57 prostates to clarify the variations of this structure. Fifty prostates were dissected under a surgical microscope, five prostates were used for ultrasonography and dissection, and two others were processed for light microscopy and reconstructed into 3D models. The PU was classified into three types based on the location of its pouch. The most common type was one in which the PU projected out from between the two ejaculatory ducts. The site and shape of the utricular orifice were also diverse on the seminal colliculus, which was most commonly located on the distal three-fourths of the prostatic urethra. The results of this study clarified the variations in the anatomy of the PU and may help improve diagnosis and treatment of PU diseases.

(c) 2009 Wiley-Liss, Inc. PMID 19173260


Regulation of Epithelial Branching Morphogenesis and Cancer Cell Growth of the Prostate by Wnt Signaling


Quantification of expression of netrins, slits and their receptors in human prostate tumors

Int J Cancer. 2003 Jan 20;103(3):306-15. Latil A, Chêne L, Cochant-Priollet B, Mangin P, Fournier G, Berthon P, Cussenot O.

UroGene, Génopole, Evry Cedex, France.


Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over-expressed either Slit genes or their receptors, Robo.

Copyright 2002 Wiley-Liss, Inc. PMID 12471613


Role of canine basal cells in postnatal prostatic development, induction of hyperplasia, and sex hormone-stimulated growth; and the ductal origin of carcinoma

Prostate. 2001 Aug 1;48(3):210-24.

Leav I, Schelling KH, Adams JY, Merk FB, Alroy J.

Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. Corrected and republished from:

Prostate. 2001 May 15;47(3):149-63. Abstract BACKGROUND: The canine prostate has often been proposed as a model for abnormal growth of the human gland. Hyperplasia of the prostate is common in aging men and has been estimated to be present in 100% of old intact dogs. While prostatic carcinoma is common in older men, it appears to be rare in dogs and unlike the disease in humans, it occurs with relatively high frequency in castrated animals. Since basal cells are thought to be key participants in normal and abnormal growth of the human gland, we used immunohistochemistry to investigate the role that they may play in canine prostatic development, the evolution of hyperplasia and carcinoma, and the effects of sex hormones on these cells.

METHODS: Prostate specimens were obtained at autopsy from seven sexually immature dogs, autopsy and biopsy samples from 14 sexually mature intact animals, from four castrates, and from19 dogs with prostatic carcinoma. In addition, we also studied the prostates from two intact dogs treated with 5alpha-dihydrotestosterone (DHT) for 6 months and two castrated dogs that were subsequently treated with 5alpha-androstane-3alpha diol and estradiol-17alpha, as well as specimens from two sexually ablated animals given DHT for 2 weeks. All specimens were immunostained for high molecular weight cytokeratin (HMC), pancytokeratin, androgen receptor (AR), and the proliferative marker KI-67.

RESULTS: We find that basal cells are the major proliferative cell type in the neonatal and adult canine prostate and that the expression of HMC staining, which defines these cells, may be regulated by androgens. In the adult gland, ductal basal cells formed a contiguous layer, whereas those lining acini were discontinuous. Populations of both basal cell types were variably AR positive, but while HMC immunostaining was abolished in acinar cells following long-term castration, staining remained in ductal cell counterparts. Paralleling the histological development of hyperplasia, the acinar basal cell population increased with age and were the major cell type that expressed KI-67. In contrast, ductal basal cell populations did not expand in the prostates of older dogs and were seldom positively stained for KI-67. The numbers of HMC and KI-67-stained acinar basal cells were dramatically increased in the prostates of intact dogs treated with DHT when compared with glands of untreated controls. This was not the case with ductal basal cells. Androgens given alone or together with estrogen to castrated dogs induced widespread HMC and KI-67 immunostaining in both populations of basal cells. In addition, our results indicate that the majority of canine prostatic carcinomas likely arise exclusively from ductal epithelium. Only one of the 19 cases of carcinoma contained cells that expressed AR, which suggests that androgens may not be required for the initiation or progression of these cancers.

CONCLUSIONS: Our findings indicate that two biologically distinct populations of basal cells may exist in the canine prostate. In this regard, the age-related expansion of proliferating acinar basal cell populations, probably mediated by sex steroids, is a key factor in the pathogenesis of canine prostatic hyperplasia. Additionally, we find that prostatic carcinoma in the dog likely arises from ductal cells. Taken together, these findings may indicate that canine acinar basal cells and ductal epithelium have separate susceptibilities to factors that promote hyperplastic or neoplastic development.

Copyright 2001 Wiley-Liss, Inc. PMID 11494337

Seminal Vesicle

Morphology and functions of the human seminal vesicle

Andrologia. 1992 Jul-Aug;24(4):183-96.

Aumüller G, Riva A.

Department of Anatomy and Cell Biology, Philipps University, Marburg, Germany. Abstract The seminal vesicles originate in embryos of about 58 mm crown-rump-length from the Wolffian duct under the influence of testosterone. Along with the ampulla of the vas deferens and the ejaculatory duct, they form a functional unit that develops slowly until the onset of puberty. Developmental malformations occur as uni- or bilateral agenesis, aplasia, cysts, or ureterovesicular fistules. After puberty, the glands form sac-like structures which have a capacity of about 3.4-4.5 ccm and contribute about 70% of the seminal fluid. In addition to secretion, they are capable of reabsorption of fluids or dissolved substances, and of spermatophagy (ingestion and degradation of damaged spermatozoa by epithelial cells). Secretory activity of the glands is a measure of testosterone supplementation to the epithelium. Nervous regulation of secretion is realized by cholinergic post-ganglionic, sympathetic (and perhaps parasympathetic) fibres, derived from pelvic plexus. Contraction of the muscular wall occurs under the influence of excitatory adrenergic and modulatory NPY-encephalin-peptidergic nerve fibres. The secretory products of the seminal vesicles encompass (1) ions (K+: 1.1 mM ml-1) (2) low molecular weight substances (fructose: above 1.2 mg ml-1; prostaglandins above 250 microliters ml-1, (3) peptides (endorphin: 330 pg ml-1), and (4) proteins. In addition to plasma protein related forms such as transferrin, lactoferrin, and fibronectin, specific proteins such as semenogelin (52 kDa) are synthesized, the scaffold protein of semen coagulate forming the substrate for PSA (prostate specific antigen), sperm motility inhibitor (ca. 18 kDa), and others (placental protein 5, protein kinase inhibitor, carboanhydrase, 5'-nucleotidase), some of which are immunosuppressive. Therefore, functions of the seminal vesicles concern (a) formation of seminal coagulum, (b) modification of sperm functions (motility, capacitation), and (c) immunosuppression. Additional functions within the female genital system, perhaps during pre-implantation period, are likely, but remain to be proven experimentally.

PMID: 1642333