The long-term goal of our laboratory is to understand how the anterior part of the mammalian brain, the telencephalon, is shaped and wired during development. The telencephalon, comprising the cerebral cortex and basal ganglia, plays essential roles such as motor control, sensory perception, and cognitive functions. Its complex neuronal networks are assembled during embryogenesis and remodeled during early postnatal life. During this process, both cell migration and axon guidance play essential roles by controlling the accurate positioning of neuronal subtypes and the formation of specific connections, respectively. Whereas conserved sets of factors have been shown to control cell migration and axon guidance, there is still much to learn about how these two fundamental processes are controlled and coordinated to ensure the morphogenesis of neural circuits in vivo.
By combining mouse molecular genetics, ex-vivo manipulations and advanced imaging techniques, we investigate how cell migration and axon pathfinding are controlled and coordinated to ensure the morphogenesis of neural networks in the developing telencephalon. As developmental abnormalities participate in the etiology of several neuropsychiatric disorders, understanding how the telencephalon wires is essential not only to gain insights into its normal functioning, but also to advance our comprehension of neuropsychiatric disorders.
We have recently shown that cell migration and axon guidance are intriguingly coordinated to ensure the formation of a major axonal tract of the mouse forebrain. Thalamocortical projections play a central role in brain functioning: they relay sensory information of distinct modalities (vision, audition, somatosensory information) to different cortical areas. Nevertheless, all thalamic axons grow within the large tract of the internal capsule together with cortical axons, thereby forming the main input/output system of the cerebral cortex. We have shown that the early pathfinding of thalamocortical projections in the internal capsule is guided by a neuronal migration within the basal ganglia of “corridor cells”. These results revealed a novel role of cell migration at intermediate targets in axon guidance and raised the questions of the mechanisms underlying this remarkable process and how it relates to forebrain wiring.
We are currently addressing these issues by performing 4 related research projects, in which we are seeking to: i) decipher the roles of basal ganglia cell migration in the guidance of thalamocortical projections; ii) understand how migrating cells and navigating axons integrate multiple environmental guidance cues in vivo to reach their final target; iii) investigate the transcriptional control of cell migration and its role in telencephalic morphogenesis and functioning; iv) determine how early defects in cell migration/thalamocortical axon guidance or in sensory input impact on the formation of mature circuits.
The results that will derive from our work will allow us to understand how complex cellular and molecular interactions that occur in the developing embryo shape neural circuits in a functionally essential region of the mammalian brain.
Lokmane L, Proville R, Narboux-Nême N, Györy I, Keita M, Mailhes C, Léna C, Gaspar P, Grosschedl R, Garel S. Sensory map transfer to the neocortex relies on pre-target ordering of thalamic axons. Curr Biol 2013 ; 23:810-6.
Deck M, Lokmane L, Chauvet S, Mailhes C, Keita M, Niquille M, Lebrand C, Yoshida M, Yoshida Y, Mann F, Grove E, Garel S. Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections. Neuron 2013 ; 77 :472-84.
Bielle° F, Marcos-Mondéjar P, Leyva-Díaz E, Lokmane L, Mire E, Mailhes C, Keita M, García N, Tessier-Lavigne M, Garel S, López-Bendito G. Emergent growth cone responses to combinations of slit1 and netrin 1 in thalamocortical axon topography. Curr Biol. 2011 Oct 25; 21(20):1748-55.
Bielle F, Marcos-Mondejar P, Keita M, Mailhes C, Verney C, Nguyen Ba-Charvet K, Tessier-Lavigne M, Lopez-Bendito G, Garel S. Slit2 activity in the migration of guidepost neurons shapes thalamic projections during development and evolution. Neuron. 2011 Mar 24; 69(6):1085-98.
Lopez-Bendito G., Cautinat A., Sanchez J.A., Bielle F., Flames N., Garrat A.N., Talmage D., Role L.W., Charnay P., Marin O., Garel S. , Tangential neuronal migration controls axon guidance : a role for neuregulin- 1 in thalamocortical axon navigation. Cell (2006), 125 — 127-42.