Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
Anna Cariboni, … , Fanny Mann, Christiana Ruhrberg
Anna Cariboni, … , Fanny Mann, Christiana Ruhrberg
Published June 1, 2015; First published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2413-2428. https://doi.org/10.1172/JCI78448.
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Research Article Development Endocrinology Genetics Neuroscience

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Abstract

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1–dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.

Authors

Anna Cariboni, Valentina André, Sophie Chauvet, Daniele Cassatella, Kathryn Davidson, Alessia Caramello, Alessandro Fantin, Pierre Bouloux, Fanny Mann, Christiana Ruhrberg

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Figure 6

PLXND1 is dispensable for axonal and vascular patterning in the embryonic mouse nose.

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PLXND1 is dispensable for axonal and vascular patterning in the embryoni...
(A) PLXND1 expression in E12.5 mouse nose. Sagittal sections of E12.5 WT heads, immunolabeled for PLXND1 and the OLF/VN axonal marker peripherin (top panels) or the vascular marker IB4 (bottom panels); sections were counterstained with DAPI. Higher-magnification images of the areas indicated with dotted squares are shown in the adjacent panels. The clear arrow indicates a PLXND1-positive axon and the solid arrow a PLXND1-positive blood vessel. (B) PLXND1 expression in E14.5 mouse nose and brain. Coronal sections of E14.5 WT nose (top panels) and MPOA (bottom panels), immunolabeled for PLXND1 and peripherin; sections were counterstained with DAPI. Higher-magnification images of the areas indicated by dotted boxes are shown in the adjacent panels. PLXND1 expression in axons in the nose and OLF bulbs (OB) is indicated with arrowheads. Note PLXND1 expression by GnRH neurons in the MPOA (clear arrow), but not by the caudal branch of the VN nerve (clear arrowhead). 3v, third ventricle. (C and D) Normal nasal axon and nasal/brain blood vessel patterning in Plxnd1-null mutants. Coronal sections of E14.5 mouse heads of the indicated genotypes at the level of the nose (top panels) and MPOA (bottom panels) were immunolabeled for peripherin and counterstained with DAPI (C) or labeled with the blood vessel marker IB4 (D). Dotted lines indicate forebrain boundaries. Scale bars: 150 μm (A–D), 50 μm (higher-magnification images of boxed areas in A and B).