Intermediate mesoderm

Early kidney structures include the pronephros and mesonephros, whose complexity, size and duration can vary greatly between vertebrate species.[1] The adult kidney, also referred to as the metanephric kidney, forms at the posterior end of the intermediate mesoderm after the degeneration of previous, less complex kidney structures.[1]

During early development (approximately day 22 in humans), the pronephric duct forms from the intermediate mesoderm, ventral to the anterior somites. The cells of the pronephric duct migrate caudally whilst inducing adjacent mesenchyme to form the tubules of the initial kidney-like structure called the pronephros.[6] This process is regulated by Pax2/8 markers.[7] The pronephros is active in adult forms of some primitive fish and acts as the primary excretory system in amphibious larvae and embryonic forms of more advanced fish.[8] In mammals however, the pronephric tubules and the anterior portion of the pronephric duct degenerates in 3.5 weeks to be succeeded by the mesonephros, the embryonic kidney.[6]

The mesonephros is constituted of a set of new tubules formed from the lateral and ventral sides of the gonadal ridge joining the cloaca.[5] The mesonephros functions between the 6th and 10th weeks of embryological life of mammals as a temporary kidney, but serves as the permanent excretory organ of aquatic vertebrates. By 8 weeks post-conception, the human mesonephros reaches maximum size and begins to regress, with complete regression occurring by week 16.[6] Despite its transiency, the mesonephros is crucial for the development of structures such as the Wolffian duct (or mesonephric duct), which in turn gives rise to the ureteric bud of the metanephric kidney.[9]

The permanent kidney of amniotes, the metanephros, develops during the 10th week in human embryos and is formed by the reciprocal interactions of the metanephrogenic blastema (or metaneophrogenic mesenchyme) and the ureteric bud.[6] Gonadal derived neurotrophic factor (GDNF) secreted by the metanephrogenic blastema activates the receptor tyrosine kinase RET, via the co-receptor GFRα1 and triggers outgrowth of Ret positive cells from the nephric duct towards the GDNF signal, promoting ureteric bud outgrowth and invasion.[1] Once the bud invades the metanephrogenic blastema, a permissive signal in the form of Wnt proteins is activated and stimulates the condensation of metanephric mesenchymal cells around the ureteric bud tips, beginning the polarisation of the blastema to generate the epithelial cells of parts of the nephron: the proximal tubules, loops of Henle and the distal convoluted tubules.[1] The ureteric bud secretes FGF2 (fibroblast growth factor 2) and BMP7 (bone morphogenic protein 7) to prevent apoptosis in the kidney mesenchyme.[2] Condensing mesenchyme then secretes paracrine factors that mediate branching of the ureteric bud to give rise to the ureter and collecting duct of the adult kidney.[10]

Wilms’ tumor (WT), also known as nephroblastoma, is an embryonic tumor originating from metanephric blastemal cells that are incapable of completing the mesenchymal-epithelial transition (MET), a crucial process during kidney differentiation involving the transition from a multipolar, spindle-shaped mesenchymal cell to a planar assembly of polarized epithelial cells.[11] As a consequence, WTs have a triphasic histology composed of three morphogenically distinct cell types: undifferentiated blastemal cells, epithelial cells, and stromal cells.[11] The Wnt/βcatenin signalling pathway is crucial for initiating MET, where specifically the WNT4 protein is required for induction of epithelial renal vesicles and the transition from mesenchymal to epithelial cells.[12] WTs are often a result of a genetic deletions or inactivating mutations in WT1 (Wilms tumor 1), which subsequently inhibits Wnt/βcatenin signalling and prevents MET progression.[11][12]

Persistent Mullerian duct syndrome (PMDS) is a congenital disorder of male sexual development and is a form of pseudohermaphroditism. Males with PMDS retain normal male reproductive organs and external genitalia, but also possess internal female reproductive organs such as the uterus and fallopian tubes.[13] PMDS is primarily caused by a mutation in the Anti-Mullerian hormone (AMH) gene (PMDS Type 1) or AMHR2 gene (PMDS Type 2). In PMDS Type 1, AMH is either not produced, produced in deficient quantities, defective, or secreted at the wrong critical time for male differentiation. PMDS Type 2 is a result of AMH receptor insensitivity to AMH molecules.[14] In a smaller percentage of cases, the cause of PMDS is not fully understood but is related to complex malformations of the urogenital region and paramesonephric ducts during male gonadal development.[13]