ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This research identifies a role for SEMA6A in puberty onset by regulating median eminence vascular permeability.

The authors elegantly use murine transgenics of Sema6a -/- combined with cell biology, biochemical assays and human genetics to identify a previously unknown role for Sema6a in regulating vascular permeability of endothelial cells within the median eminence (ME) to maintain neuroendocrine homeostasis. The role of SEMA6A in regulating the timing of puberty in humans is further demonstrated by the identification of a novel functional genetic variant, SEMA6A I423T in patients with delayed puberty (DP).

To support their findings, the authors first performed a thorough analysis of the embryonic and adult expression of Sema6a. Sema6a is the cell surface receptor for Plexin-A2 involved in several functions from cell migration to differentiation. In early development, Sema6a was not expressed by the GnRH neurons but instead strong expression was identified in the ME in close proximity to the axonal terminals at late gestation. Interestingly, mice lacking Sema6a exhibited normal GnRH neuronal migration but presented with a reduction of GnRH innervation at the ME. Moreover, the canonical Sema6a receptors, Plexin-A2 and Plexin-A4 were not detected in GnRH neurons, suggesting that Sema6a could function through other cell types. Analyses of Sema6a^-/- male and female mice showed delayed puberty onset and sexual maturation defects. The number of GnRH neurons was unaffected in mice lacking Sema6a but ME innervation was reduced in both sexes.

The authors identify the source of Sema6a is the oligodendrocytes (OLs) involved in ME homeostasis. The hypothesis that Sema6a may regulate ME vascular permeability was then tested by analysing the trans-endothelial electrical resistance using in vitro cell cultures of ECs treated with extracellular Sema6a. Importantly, the authors show that Sema6a acts as a potent inducer of endothelial permeability in vitro. Sema6a null mice exhibit reduced fenestrated capillaries in the ME. Further analyses of 100 human probands with delayed puberty (DP) using exome sequencing identified a genetic variant, SEMA6A I423T, that leads to self-limited delayed puberty. This variant is shown to be pathogenic using in silico tools combined with cellular and biochemical assays to identify the effect of this newly DP-associated genetic variant on the development of the GnRH neuroendocrine network in humans.

In conclusion, this excellent study provides compelling evidence that SEMA6A acts as a critical regulator of puberty onset by controlling the permeability of blood vessels in the median eminence. By ensuring the proper timing of GnRH secretion, SEMA6A regulates the orderly progression of sexual maturation. This discovery not only deepens our understanding of the genetics of neuroendocrine control of puberty in humans but also opens new possibilities for therapeutic intervention in puberty-related disorders.