Yesser Hadj Belgacem Tellier

Sonic hedgehog signaling is critical for early patterning of the central nervous system during early phases of development. The roles it plays later in development, maturation and physiology of the brain are, however, largely unknown. Discovering these roles is therefore crucial and may help us understand better certain pathologies affecting the central nervous system.

Sonic hedgehog (Shh) signaling pathway plays a major role in development and patterning of the central nervous system (CNS). Upon binding to its receptor, Shh triggers a cascade of signaling events leading to recruitment of the main effectors of the canonical signaling pathway, the Gli family of transcription factors that, in turn, lead to the expression of target genes. Shh is mostly known for its morphogenetic role during development where it establishes the dorso-ventral axis of the neural tube. Lately, several non-canonical, Gli-independent Shh signaling pathways have been identified, which has led to the discovery of new and unpredicted roles for Shh signaling. We recently demonstrated that Shh modulates spontaneous calcium-based electrical activity of developing spinal neurons, leading to homeostatic control of neurotransmitter specification. Given the importance of spontaneous electrical activity during CNS development and the fact that Shh signaling components are still expressed in the postnatal CNS, long after patterning has occurred, the discovery of this novel interaction suggests new roles for Shh signaling yet to be discovered.

γ-amino butyric acid (GABA) is the main inhibitory neurotransmitter in the adult brain. Interestingly, GABA plays critical roles during CNS development and maturation. The Marseille-based research group of Dr. Jean-Luc Gaiarsa pioneered research on the role of developmental forms of GABAergic synapse plasticity that highlighted its importance on neural network formation and proper maturation, particularly in the postnatal hippocampus. Drs. Gaiarsa’s and Ben-Ari’s groups (Marseille, INMED) have further demonstrated the importance of developmental plasticity of GABAergic synapses to neurodevelopmental pathologies such as memory deficits, epilepsy and autism spectrum disorders (ASD).

Intriguingly, Shh and its coreceptors Patched (Ptc) and Smoothened (Smo) are present at GABAergic synapses in the postnatal hippocampus in rodents. Our interdisciplinary project, taking place at the IMERA, will focus on discovering the role of Shh signaling on developmental synapse plasticity and understand its physiological and pathological consequences to CNS function.