Crucial sex hormones re-routed by missing molecule

An optical section through a normal mouse nose showing the route the nerve cables (yellow) normally transport the GnRH through the nose (blue). The red shows the corridor inside the nose through which the nerve cables like to travel. (Credit: Dr Anna Cariboni)

A hormone responsible for the onset of puberty can end up stuck in the wrong part of the body if the nerve pathways responsible for its transport to the brain fail to develop properly, according to new research led by UCL scientists.

By tracking how nerve cells responsible for regulating sexual reproduction in mice find their way from their birth place in the foetal nose to their site of action in the adult brain, the researchers found that if a certain molecule is missing, then these pathways are not formed correctly and gonadotropin releasing hormone (GnRH) can become lodged in the nose or the forehead rather than in the brain, where it is needed to control the menstrual cycle in females and testosterone production in males.

Speaking about the findings, published today in Human Molecular Genetics and funded by the Biotechnology and Biological Sciences Research Council (BBSRC), co-investigator Dr Christiana Ruhrberg (UCL Institute of Ophthalmology) explains: ’We discovered that a molecule essential for the growth of the nerve cables that transmit odour and pheromone signals from the nose to the brain is also crucial in the development of the highways responsible for transporting other nerve cells that make the sex hormone GnRH.

"We found that in mice with an inherited deficiency in the molecule SEMA3A, these highways did not lead to the brain, but instead formed impenetrable tangles outside the brain. This means that the nerve cells making GnRH are unable to get to their final destination and instead become stuck in the nose or forehead.’

As a result the researchers found that the testes of mice lacking SEMA3A did not grow properly and the adult males were infertile. These findings have important implications for the study of Kallmann’s syndrome and related genetic disorders that cause infertility.

Professor Douglas Kell, BBSRC Chief Executive said ?This study highlights the importance of understanding the very earliest developmental processes of the brain, including how and where cells develop, how they migrate and how and where they mature. Such fundamental bioscience research helps drive medical advances by providing clues about the development of a variety of disorders which present huge challenges to individuals, their families and our wider society.’

The UCL Institute of Ophthalmology aims to develop new treatments for eye disease out of a large and varied foundation of basic research. Its researchers work very closely with Moorfields Eye Hospital NHS Foundation Trust and are part of UCL Biomedicine, one of the largest aggregates of biomedical expertise in the world.

The range of diseases studied extends from inherited retinal degenerations affecting young children to age-related macular degeneration and glaucoma, the most common causes of blindness in the elderly. Currently groups are investigating every stage of the visual process from the mechanics of rods and cones to the brain‘s interpretation of complex visual scenes. The institute’s researchers are making progress in understanding the basic mechanisms of blinding disease and investigating new methods of treatment by conventional pharmacology, gene therapy and cellular therapy including stem cells.

Moorfields Eye Hospital, Great Ormond Street Hospital for Children, UCLH, the Royal Free and UCL together form UCL Partners, Europe’s largest academic health science partnership.

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