RESUMEN
The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15-Vps34 complex and the Nischarin-Pak1 signaling hub in the development of the telencephalon.
Asunto(s)
Movimiento Celular/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Mutación/efectos de los fármacos , Trastornos del Neurodesarrollo , Neuronas/patología , ATPasas de Translocación de Protón Vacuolares/genética , Alquilantes/toxicidad , Animales , Animales Recién Nacidos , Atrofia/inducido químicamente , Atrofia/genética , Atrofia/patología , Autofagia/efectos de los fármacos , Autofagia/genética , Encéfalo/efectos de los fármacos , Encéfalo/patología , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Embrión de Mamíferos , Etilnitrosourea/toxicidad , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastornos del Neurodesarrollo/inducido químicamente , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , ATPasas de Translocación de Protón Vacuolares/efectos de los fármacosRESUMEN
In the supplementary information PDF originally posted, there were discrepancies from the integrated supplementary information that appeared in the HTML; the former has been corrected as follows. In the legend to Supplementary Fig. 2c, "major organs of the mouse" has been changed to "major organs of the adult mouse." In the legend to Supplementary Fig. 6d,h, "At E14.5 Mbe/Mbe mutants have a smaller percentage of Brdu positive cells in bin 3" has been changed to "At E14.5 Mbe/Mbe mutants have a higher percentage of Brdu positive cells in bin 3."