We recently described the role of a group of neural guidance molecules, the Semaphorins in the development of hypothalamic brain circuits that regulate body weight.
We characterised rare genetic variants affecting the function of multiple genes encoding the Semaphorin3 ligands, receptors and co-receptors. Deletion of these genes in zebrafish caused increased growth and/or adiposity and deletion of the Semaphorin receptor, Neuropilin-2, in the hypothalamus caused mis-wiring in the hypothalamus and weight gain in mice. The human variants reduced the ability of these molecules to guide neurons precisely to their destination.
Previously, we have identified rare variants in people with severe obesity that affect the function of the brain circuits that regulate weight in the hypothalamus. In this study we have now discovered genes that establish the precise neural connections that form these circuits.
