New horizons at the caudal embryos: coordinated urogenital/reproductive organ formation by growth factor signaling

Abstract

The cloaca/urogenital sinus and its adjacent region differentiate into the urogenital/reproductive organs. Caudal regression syndrome (CRS; including mermaid syndrome), a type of severe cloacal malformation displays hindlimb fusion and urogenital organ defects, thus suggesting that such defects are caused by several morphogenetic alterations during early development. The attenuation of bone morphogenetic protein (Bmp) signaling at the posterior primitive streak of embryos leads to the caudal dysmorphogenesis including the cloaca and fusion of both hindlimbs. Genetic tissue lineage studies indicate the presence of coordinated organogenesis. Hedgehog (HH)-responding cells derived from peri-cloacal mesenchyme (PCM) contribute to the urogenital/reproductive organs. These findings indicate the existence of developmental programs for the coordinated organogenesis of urogenital/reproductive tissues based on growth factor function and crosstalk.

Figure 1. A schematic illustration showing “the developmental coordination” at the level of caudal embryos

Externally growing appendicular anlage, such as the hindlimb (purple) and external genitalia (green) and also internally developing organs (from the cloaca (red cavity) towards pelvic organs) develop in coordination. Defects in the coordination may be involved for the onset of some syndromes with abnormal organogenesis (a lower arrow). An example of a syndrome displaying such abnormalities including bladder and external genital defects (EEC as an example; exstrophy and epispadias complex). Pathological mechanisms of EEC is largely unknown. The defects in the developmental coordination of PCM derived cells may constitute one of the causal factors. Developmental coordination also includes proper regulation of cell-supply through EMT from the developing VER (ventral ectodermal ridge) and the PS, which are close to the tail bud. Dysregulation of such cell supply has been suggested to cause hindlimb fusion and reduction of the “cloacal field”. PCM, peri-cloacal mesenchyme.

Figure 2. Contribution of HH responding cells in the formation of urogenital organs

(A) One of the key epithelial growth factors expressed at the cloacal membrane (CM) is Shh. Shh expression is first detected prominently in the endoderm including the cloaca. (B) Its expression continues to several epithelial regions derived from cloaca, towards the urethral plate (UP), the pelvic urethra and the bladder lumen. (C) Genetic lineage analysis revealed the tissue contribution from the PCM towards the dorsal external genitalia and bladder mesenchyme (smooth muscle) [15]. PCM, peri-cloacal mesenchyme; CM, cloacal membrane; GT, genital tubercle; UP, urethral plate; DUE, distal urethral epithelium.