SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability

Antonella Lettieri, Roberto Oleari, Marleen Hester Munkhof, Eljo Yvette Battum, Marieke Geerte Verhagen, Carlotta Tacconi, Marco Spreafico, Alyssa Julia Jennifer Paganoni, Roberta Azzarelli, Valentina Andre’, Federica Amoruso, Luca Palazzolo, Ivano Eberini, Leo Dunkel, Sasha Rose Howard, Alessandro Fantin (), Ronald Jeroen Pasterkamp () and Anna Cariboni ()
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Antonella Lettieri: University of Milan
Roberto Oleari: University of Milan
Marleen Hester Munkhof: University Medical Center Utrecht Brain Center, Utrecht University
Eljo Yvette Battum: University Medical Center Utrecht Brain Center, Utrecht University
Marieke Geerte Verhagen: University Medical Center Utrecht Brain Center, Utrecht University
Carlotta Tacconi: University of Milan
Marco Spreafico: University of Milan
Alyssa Julia Jennifer Paganoni: University of Milan
Roberta Azzarelli: University of Cambridge
Valentina Andre’: University of Milan
Federica Amoruso: University of Milan
Luca Palazzolo: University of Milan
Ivano Eberini: University of Milan
Leo Dunkel: Queen Mary University of London
Sasha Rose Howard: Queen Mary University of London
Alessandro Fantin: University of Milan
Ronald Jeroen Pasterkamp: University Medical Center Utrecht Brain Center, Utrecht University
Anna Cariboni: University of Milan

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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 identify patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset.

Date: 2023
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DOI: 10.1038/s41467-023-43820-z

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