ESPE2023 Symposia What's new for the HPG Axis (3 abstracts)
SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability
Anna Cariboni 1 , Roberto Oleari 1 , Antonella Lettieri 1 , Marleen van den Munkhof 2 , Eljo van Battum 2 , Carlotta Tacconi 1 , Marco Spreafico 1 , Alyssa Paganoni 1 , Federica Amoruso 1 , Ivano Eberini 1 , Leonard Dunkel 3 , Alessandro Fantin 4 , Sasha Howard 3 & Jeroen Pasterkamp 2
1University of Milan, Milan, Italy. 2Utretch Medical Center, Utrecht, Netherlands. 3Queen Mary University of London, London, United Kingdom. 4University of Milan, Milan, United Kingdom
Innervation of the hypothalamic median eminence by Gonadotropin-Releasing Hormone (GnRH) neurons is vital to ensure puberty onset and successful reproduction. However, the molecular and cellular mechanisms underlying median eminence development and pubertal timing are incompletely understood. Here we show that Semaphorin-6A is strongly expressed by median eminence-resident oligodendrocytes positioned adjacent to GnRH neuron projections and fenestrated capillaries, and that Semaphorin-6A is required for GnRH neuron innervation and puberty onset. in vitro and in vivo experiments reveal an unexpected function for Semaphorin-6A, via its receptor Plexin-A2, in the control of median eminence vascular permeability to maintain neuroendocrine homeostasis. To support the significance of these findings in humans, we identified patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a novel role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset.
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