Molecular regulation of neurogenesis in health and disease
The goal of our research is to identify fundamental mechanisms that regulate cerebral neurogenesis. Our team uses a combination of genetic, molecular and cellular techniques to : 1/ untangle the regulatory mechanisms of cerebral cortex neurogenesis and, 2/ to shed some light on the pathological mechanisms that affect neurogenesis in neurological disorders. To achieve these goals, we are using several approaches divided into two major topics :
I/Cellular and molecular regulations of cerebral cortical development.
The cerebral cortex emerges from bisymmetrical telencephalic vesicles of the developing forebrain and contains neurons that are distributed within layers and are regionally organized into specialized areas that underlie sophisticated motor, cognitive and perceptual abilities. Cortical lamination follows an « inside-out » sequence of neuronal placement and maturation that arises from the sequential birth and orderly migration of pyramidal projection neurons born in the dorsal telencephalon and, GABAergic interneurons generated in the ganglionic eminences. Both populations of neurons actively migrate into the developing cortex, with projection neurons engaging primarily in radial migration, while interneurons undergo tangential migration, travelling along a oblique paths via specified routes to reach the cortical plate. The development of the cortex progresses through several stages including, neural proliferation, neuroblast migration and neuronal differentiation. Disrupting the completion of one or several of these steps often cause cortical malformations that lead to severe learning disabilities, mental retardation and epilepsy. Thus, identification of new molecular pathways that promote the formation of the cortex is critical to interpret the pathological mechanisms that contribute to the onset and the progression of neurological disorders.
II/ Molecular basis of neurodevelopmental and neurodegenerative diseases
Neurodegenerative disorders are associated with the progressive loss of selective cell populations in the central and/or the peripheral nervous system. We are currently facing new challenges to prevent and cure these diseases that are widespread in our aging society. In addition, the huge cost of these disorders calls for increased efforts in research to find the mechanisms that are responsible for the onset or the progression of neurodegenerative disorders.
Selected references from our lab
Gladwyn-Ng I, Cordón-Barris L, Alfano C, Creppe C, Couderc T, Morelli G, Thelen N, America M, Bessières B, Encha-Razavi F, Bonnière M, Suzuki IK, Flamand M, Vanderhaeghen P, Thiry M, Lecuit M, and Nguyen, L . : Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly.
Nat Neurosci (2018), 21(1):63-71 (IF=17.8)
Tielens, S.*, Huysseune, S.*, Godin, J.D., Chariot, A., Malgrange, B., and Nguyen, L . : Elongator controls cortical migration by regulating actomyosin dynamics.
Cell Research (2016), 26(10): 1131-1148 (IF=15.6)
Godin, J.D., Creppe, C., Laguesse, S., and Nguyen, L. : Emerging roles for the unfolded protein response in the developing nervous system.
Trends Neurosci (2016), 39(6): 394-404 (IF=11.1)
Laguesse, S., Creppe, C., Nedialkova, D., Prévot, P.-P., Borgs, L., Huyseune, S., Franco, B., Duysens, G., Krusy, N., Lee, G., Thelen, N., Thiry, M., Close, P., Chariot, A., Malgrange, B., Leidel, S., Godin, J., and Nguyen, L. : A dynamic unfolded protein response contributes to the control of cortical neurogenesis
Dev Cell (2015), 35(5): 553-567 (IF=9.7)
Volvert, M.-L., Prévot, P.-P., Close, P., Laguesse,S., Pirotte, S., Hemphill, J., Rogister, F., Kruzy, N., Sacheli, R., Moonen, R., Deiters, A., Merkenschlager, M., Chariot, A., Malgrange, B., Godin, J., and Nguyen, L. : MicroRNA Targeting of CoREST Controls Polarization of Migrating Cortical Neurons,
Cell Rep (2014), 7(4): 1168-83 (IF=8.4)
Avila, A., Vidal, P.M., Dear, T.N., Harvey, J.H.., Rigo, J.-M., and Nguyen, L. : Glycine receptor α2 subunit activation promotes cortical interneurons migration.
Cell Rep (2013), 21(11): 1696-1708 (IF=7.2)
Godin, J., Thomas, N., Laguesse, S., Malinouskaya, L., Close, P., Malaise, P., Purnelle, A., Raineteau, O., Campbell, K., Fero, M., Moonen, G., Malgrange, B., Chariot, A., Metin, C, Besson, A., and Nguyen, L.: p27Kip1 is a microtubule-associated protein that promotes microtubule polymerisation during neuron migration.
Dev Cell (2012), 23 (4): 729-44 (IF=12.9)
Westerlund, N., Zdrojewska, J., Padzik, A., Komulainen, E., Bjôrkblom, B., Tararuk, T., Garcia-Frigola, C., Sandholm, J., Nguyen, L., Kallunki, T., Courtney, M.J., and Coffey, E. : SCG10/Stathmin phosphorylation determines the duration of multipolar stage and migration speed.
Nat Neurosci (2011), 14(3): 305-13. (IF=15.5)
Heng, J.I.-T., Chariot, A., and Nguyen, L. : Molecular layers underlying cytoskeleton remodeling during cortical development.
Trends Neurosci (2010), 33(1): 38-47 (IF=13.3)
Godin, J., Colombo, K., Charrin, B., Keryer, G., Volvert, M.-L., Guillemot, F., Bellaiche, Y., Saudou, F., Nguyen, L., and Humbert, S. : Huntingtin is required for proper Spindle Orientation during mitosis in Drosophila and Mammals.
Neuron (2010), 67: 1-15 (IF=14.0)
Nguyen, L., Humbert, S., Saudou, F., and Chariot, A. : Elongator - an emerging role in different neurological diseases.
Trends Mol Med (2010), 16(1): 1-6 (IF=10.3)
De Nijs, L., Léon, C., Nguyen, L., LoTurco, J.J., Delguado-Escuata, A.V., Grisar, T., and Lakaye, B. : EFHC1 interacts with microtubules to regulate cell division and cortical development.
Nat Neurosci (2009), 12(10): 1266-74. (IF=14.3)
Creppe, C., Malinouskaya, L., Volvert, M.-L., Gillard, M., Close, P., Malaise, O., Laguesse, S., Cornez, I., Rahmouni, S., Ormenese, S., Belachew, S., Malgrange, B., Chapelle, J.-P., Siebenlist, U., Moonen, G., Chariot, A. and Nguyen, L. : Elongator Controls the Migration and Differentiation of Cortical Neurons through Acetylation of Alpha Tubulin.
Cell (2009), 132: 551-564 (IF=31.2)
Heng, J.I.-T, Nguyen, L., Castro, D., Zimmer, C., Skowronska-Krawczyk, D., Bedogni, F., Matter, J.-M., Hevner, R., Guillemot, F. : Neurogenin2 controls cortical neuron migration through regulation of Rnd2.
Nature (2008), 455 (7209): 114-8 (IF=31.5)
Nguyen, L., Besson, A., Heng, J.I.-T, Schuurmans, C., Teboul, L., Parras, C., Philpott, A., Roberts, J.M., and Guillemot, F.: p27Kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.
Genes Dev (2006), 20(11): 1511-24 (IF=15.1)