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Modeling development of genitourinary birth defects to understand disruption due to changes in gene dosage - PubMed

  • ️Sat Jan 01 2022

Review

. 2022 Dec 25;10(6):412-424.

eCollection 2022.

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Review

Modeling development of genitourinary birth defects to understand disruption due to changes in gene dosage

Victor A Ruthig et al. Am J Clin Exp Urol. 2022.

Abstract

Genitourinary development is a delicately orchestrated process that begins in the embryo. Once complete, the genitourinary system is a collection of functionally disparate organs spread throughout the abdominal and pelvic regions. These distinct organs are interconnected through an elaborate duct system which aggregates the organs' products to a common exit point. The complicated nature of the genitourinary system makes it highly susceptible to developmental disruptions that produce anomalies. In fact, genitourinary anomalies are among the most common class of human birth defects. Aside from congenital anomalies of the kidney and urinary tract (CAKUT), for males, these birth defects can also occur in the penis (hypospadias) and testis (cryptorchism), which impact male fertility and male mental health. As genetic technology has advanced, it has become clear that a subset of cases of genitourinary birth defects are due to gene variation causing dosage changes in critical regulatory genes. Here we first review the parallels between human and mouse genitourinary development. We then demonstrate how translational research leverages mouse models of human gene variation cases to advance mechanistic understanding of causation in genitourinary birth defects. We close with a view to the future highlighting upcoming technologies that will provide a deeper understanding of gene variation affecting regulation of genitourinary development, which should ultimately advance treatment options for patients.

Keywords: Microdeletion/microduplications; copy number variant (CNV); cryptorchidism; penile anomalies.

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Conflict of interest statement

DJL previously served on the scientific advisory board of Fellow Health (equity), and serves on the American Board of Bioanalysts as secretary-treasurer (Honorarium), the American Association of Bioanalysts as Section Representative (Honorarium), as a Consultant and member of the Advisory Board of Roman, Inc (Equity and Compensation). None of these are relevant for the studies presented herein. The authors state explicitly that they have no conflicts of interest relevant to the studies presented in this article.

Figures

Figure 1
Figure 1

Genitourinary development can be divided into three major perinatal periods. A: Early in fetal development the gonad (1) and genital tubercle (2) are bipotential (green) and morphologically indistinguishable between the genetic sexes. During this period the bladder (3) starts to elaborate and the mesonephros (4) derived ureteric bud (5) invades the metanephros (6) as the first step of kidney development. B: After sex determination in XY the presence of SRY initiates male reproductive tract development. This begins as the gonad is directed towards a testis (7) fate with the germ, supporting and steroidogenic cells in the testis also committing to a male (9) sex specific program (see Figure 2 for more details). Shortly after commitment to testis development testicular androgen production influences the genital tubercle towards penis (11) development. Similarly, the mesonephros and mesonephric duct (4) will complicate forming the outflow tubules that will transport sperm out of the adult testis (12, see Figure 3 for more details). C: After birth genitourinary structures of the reproductive and urinary tracts continue to elaborate into adult morphologies: adrenal gland (13), kidney (14), ureter (15), bladder (16). The male reproductive tract (blue) also further elaborates into adult structures epididymis (17), vas deferens (18), seminal vesicle (19), prostate (20), bulbourethral gland (21) with significant gross anatomical differences between the mouse penis (22), which contains a baculum (23), and prepuce (24), and human penis (25) and prepuce (26).

Figure 2
Figure 2

After gonadal sex determination in the male, cell populations of the testis drive morphogenesis. (A) Diagram of the fetal testis with showing male germ cells (green), supporting cells (blue), area of steroidogenic cells (yellow), an vasculature (red, blood), which invade from the mesonephros (grey). (B) Whole mount immunofluorescent imaging of a E14.5 mouse testis with germ cells (green), supporting cells (blue), and blood supplying vasculature (red). (C) Whole mount immunofluorescent imaging of a P2 mouse testis with germ cells (green), supporting cells (blue), and blood supplying vasculature (red). (D) Cartoon diagram of the adult mouse testis (see Figure 3 for details). (E) Cross section immunofluorescent imaging of adult mouse seminiferous tubules showing different stages of active spermatogenesis (noted in Roman numerals) with developing germ cells (green) facilitated by supporting cells (blue). Scales are: 500 µm in (B and C), and 75 µm in (E).

Figure 3
Figure 3

Mouse and human testis anatomy. (A, B) Testis, epididymis and vas deferens from human (A) and mouse (B); (A) is planstinated tissue and (B) is fresh tissue. (C, D) Diagrammatic representation of human (C) and mouse (D) testis interior. The human testis is divided into a series of radiating septa that each contain a highly coiled loop of seminiferous tubule (C). The seminiferous tubules of the mouse have a pole-to-pole looping swooping structure (D). Scale is 5 cm in (A) and 5 mm in (B). Image in (A) is part of a larger dissection published in Ruthig et al. 2016 Anatomy [1] in (C) was inspired by work of Netter [111].

Figure 4
Figure 4

Classifications of hypospadias severity by urethral opening location. Hypospadias is characterized by ectopic placement of the urethral opening, which can occur distally to proximally on the penis as the severity increases (denoted by colored bars [112]). Ectopic urethra can occur in conjunction with a foreskin that has failed to fuse ventrally “hooded foreskin”, and varying degrees of chordee, curvature, of the shaft of the penis (figure inspired by Piñeyro-Ruiz 2020 Frontiers Pediatrics and informed by [19,20]).

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References

    1. Ruthig VA, Labrash S, Lozanoff S, Ward MA. Macroscopic demonstration of the male urogenital system with evidence of a direct inguinal hernia utilizing room temperature plastination. Anatomy. 2016;10:211–220. - PMC - PubMed
    1. Chughtai B, Sawas A, O’Malley RL, Naik RR, Ali Khan S, Pentyala S. A neglected gland: a review of Cowper’s gland. Int J Androl. 2005;28:74–77. - PubMed
    1. Wen JG, Lu YT, Cui LG, Bower WF, Rittig S, Djurhuus JC. Bladder function development and its urodynamic evaluation in neonates and infants less than 2 years old. Neurourol Urodyn. 2015;34:554–560. - PubMed
    1. Liaw A, Cunha GR, Shen J, Cao M, Liu G, Sinclair A, Baskin L. Development of the human bladder and ureterovesical junction. Differentiation. 2018;103:66–73. - PubMed
    1. Yiee J, Wilcox D. Abnormalities of the fetal bladder. Semin Fetal Neonatal Med. 2008;13:164–170. - PubMed

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