2014 Group Project 4
|2014 Student Projects|
|2014 Student Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7 | Group 8|
|The Group assessment for 2014 will be an online project on Fetal Development of a specific System.
This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.
|Weeks||M A L E||F E M A L E|
|FERTILIZATION||both male and female are same at this point- only difference is presence of XY or XX chromosome|
|WEEKS 1-7||GENITAL DEVELOPMENT IS UNDIFFERENTIATED. gonads derived from:
* mesothelium lining posterior abdominal wall * underlying mesenchyme * primordial germ cells.
|WEEK 5||development of indifferent gonads
|WEEK 8||seminiferous tubules begin to release androgens|
|WEEK 10||rudimental rete ovarii forms from indifferent gonads|
|WEEK 16||primordial follicles begin to develop|
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
Current Research, Models and Findings
• Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias.
• Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra.
• The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.
• Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes.
• A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect.
• The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs).
• Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.
• Future research can work to decrease the incidence of hypospadias, which has more than doubled in the past 30 years.
• Current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology.
Current model: of the cellular and molecular mechanisms of the development of mammalian external genitalia.
DEVELOPMENT OF EXTERNAL GENITALIA IN THE HUMAN
Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE
• The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings.
• These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal.
• The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane.
• These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.
• These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly and the rectum and anus posteriorly.
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• This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
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• When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
• The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.
Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION
• Initially, the female and male fetuses’ external genitalia are identical and includes the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
• In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.
• As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.
• At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
• Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
• As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra.
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• The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.
• Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
• The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis. Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
• During development, the mesoderm separates into connective tissues and dermis.
• Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.
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• Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. These two layers are then surrounded by erectile tissues such as the corpus spongiosum and corpus cavernosum.
• In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
• Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.
• Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.
• Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.
<pubmed>18367374</pubmed> <pubmed>15086026</pubmed> <pubmed>14641326</pubmed> <pubmed>11684660</pubmed> <pubmed>22127979</pubmed> <pubmed>24631756</pubmed> <pubmed>23192465</pubmed>
Female Genital Development
The mullerian (paramesonephric) ducts, found laterally to the wolffian ducts, are the original structures of the female reproductive system. Female sexual organs (the fallopian tubes, uterus and vagina) originate from the mullerian ducts, which differentiates within the foetal developmental phase. Initially the foetus contains two mullerian ducts, however by the ninth week, fusion of the lower portion of the ducts is complete, creating the fundamental structure of the uterus and the vagina, however the these two organs are not continuous with the vagina being solid. The non-fused upper part of the ducts emerge into the fallopian tubes. It is not until the fourth and fifth month of development that the uterus becomes continuous with the vagina, with both organs developing a hollow lumen. The muscular layers of the uterus is also present by this stage. The cervix begins to form within the fifth month in between the continuous vagina and uterus. Also within the same month, the formation of the hymen occurs. The hymen is described as a pouting vertical slit and represents the remains of the mullerian eminence.  
Male Genital Development
Foetal prostate differentiation begins in the 10th week of gestation, influenced by the production of testosterone that starts within the 8th week. It is discovered that the origin of the gland is from the urogenital sinus. The prostate gland continues to grow and differentiate within the foetal period and postnatally under the influence of androgens.
Prostate foetal development has been continuously reshaping at a slow rate since the published illustrations of the male sex organs by Andreas Vesalius in 1543. Throughout this period, various anatomical classifications have been proposed via dissection procedures, hormone responses and histological methods, attributing to the current understanding of prostate development. It was not until the following century that another anatomical description of the prostate was put forth. Gerard Blasius in 1674 introduced the gland as a structure encircling the neck of the bladder. Literature in relevance to the embryonic prostate was further published in the late 19th century. The literature was reviewed and compared within the subsequent 20th century articles. Research into the structure and development of the prostate continued, however the rate of publication steeply increased in the 20th century, where each decade saw an improvement of the understanding of the development of the gland.
In 1912, Oswald S Lowsley constructed the first detailed illustration of the anatomy of the prostate, and to an extent, began the research that led to today’s understanding of the sex gland. Lowsley created his model from researching on a 13-week old foetus, 30-week old foetus, and one at full-term. From examining the samples he proposed that the prostate can be divided into five lobes consisting of differing amounts of tubules. This concept was later rendered invalid, however a discovery from Lowsley that is still accepted today is that the prostate originates from the urogenital sinus.
Lowsley’s division of the prostate into lobes was questioned by Johnson in 1920, where in his research and reconstruction of the prostate, was has unable to produce identical results as Lowsley. Upon conclusion of his work he reshaped the anatomical illustration of the prostate, however preserved the use of the term lobe in describing the prostatic divisions. It was not until 1954, 42 years post the introduction of the lobe terminology, that it was completely revoked by Franks. Franks, upon dissections, described the prostate in terms of three concentric regions. Today, it is clear that the prostate consists of zones and not lobes as introduced by Lowsley nor concentric regions as introduced by Franks. The concept of prostatic zones was established by McNeal in the 1980s and is still accepted today. 
<pubmed>18462432</pubmed> <pubmed>17232227</pubmed> Martyn P. L. Williams, John M. Huston The history of ideas about testicular descent. Pediatric Surgery International: 1991, 6(3):180-184 The history of ideas about testicular descent
In males the most common congenital malformation of the external genitalia is hypospadias, it’s also the second most common developmental disorder. It occurs due to the midline fusion of the male urethra, as a result the urethral meatus is misplaced. There are several sites where this abnormality may occur: granular, penile, penoscrotal, scrotal and perineal.  Its believed that genetic factors contribute to the presence of the disorder, however endocrine and environmental factors are also of significance.  Treatment The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. For proximal forms two staged procedures are employed. 
A review on spermatogenesis and cyptorchidism a common in males, results in an absence of testes either one or both.