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The team of Prof. Jeanne Amiel and Prof. Stanislas Lyonnet has just demonstrated that the loss of function of a receptor of the Sonic Hedgehog pathway, coded by the SMO gene, and whose somatic mutations are reported in tumors, is responsible for a polymalformative syndrome affecting the development of the brain, heart, nervous system, digestive tract and skeleton. Sophie Thomas, Inserm research fellow at Imagine, and Thuy-Linh Le, who will soon defend her science thesis on the subject, explain.
What is the purpose of your research?
Sophie Thomas : The research work of the team aims to identify the genetic and embryological basis of malformations. These represent the first cause of hospitalization in pediatrics and, for almost half of them, the cause is not known.
In particular, my research focuses on ciliopathies, malformations due to a defect in the biogenesis or function of the primary cilium, an organelle present on the surface of almost all our cells and responsible for capturing and transmitting extracellular signals of various kinds.
What is your latest discovery about?
Thuy-Linh Le: We have shown that invalidation of a major player in the Sonic Hedgehog signaling pathway, the SMO gene, can cause a large number of developmental abnormalities affecting the brain, heart, skeleton and gastrointestinal tract with variable combinations that can be recognized as syndromes, classified in the group of ciliopathies
What is the function of the Sonic Hedgehog pathway?
S. T.: This signaling pathway is crucial for the embryonic development of many organs. It is captured and transmitted by the primary cilium where the Sonic Hedgehog (SHH) morphogen receptors are located. When SHH binds to the PTCH1 receptor, the latter is transported out of the cilium allowing the entry of another ciliary receptor, SMO. Thus activated, SMO triggers a series of chain reactions in the cell and activates or inhibits key genes for cell differentiation.
What part of the Hedgehog pathway is responsible for the developmental abnormalities you just discovered?
S. T.: We have demonstrated a loss of function of the SMO protein, due to an alteration of both copies of the gene, in 7 young patients from five independent families with a broad spectrum of developmental abnormalities, each previously reported in other ciliopathies. This loss of function alters the dynamics of ciliary protein entry and exit within the primary cilium, thereby disrupting the signal transmission of the Sonic Hedgehog pathway.
Our results highlight the evolutionary conservation of the crucial role of SMO during development and add it to the list of genes responsible for ciliopathies. Finally, this study reinforces the key and still insufficiently studied role of the Sonic Hedgehog pathway in the development of the nervous system of the digestive tract and in Hirschsprung's disease which is a model for the study of rare diseases of complex inheritance in the laboratory.
