RESUMEN
Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/- mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.
Asunto(s)
Trastorno Autístico/metabolismo , Haploinsuficiencia , Neocórtex/metabolismo , Red Nerviosa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Conducta Social , Animales , Trastorno Autístico/genética , Conducta Animal/fisiología , Masculino , Ratones , Mutación Missense , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Quinasas DyrKRESUMEN
BACKGROUND: The signaling cascades governing neuronal migration and axonal guidance link extracellular signals to cytoskeletal components. MAP1B is a neuron-specific microtubule-associated protein implicated in the crosstalk between microtubules and actin filaments. RESULTS: Here we show that Netrin 1 regulates, both in vivo and in vitro, mode I MAP1B phosphorylation, which controls MAP1B activity, in a signaling pathway that depends essentially on the kinases GSK3 and CDK5. We also show that map1B-deficient neurons from the lower rhombic lip and other brain regions have reduced chemoattractive responses to Netrin 1 in vitro. Furthermore, map1B mutant mice have severe abnormalities, similar to those described in netrin 1-deficient mice, in axonal tracts and in the pontine nuclei. CONCLUSIONS: These data indicate that MAP1B phosphorylation is controlled by Netrin 1 and that the lack of MAP1B impairs Netrin 1-mediated chemoattraction in vitro and in vivo. Thus, MAP1B may be a downstream effector in the Netrin 1-signaling pathway.
Asunto(s)
Axones/fisiología , Encéfalo/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Neuronas/fisiología , Transducción de Señal/fisiología , Animales , Western Blotting , Encéfalo/embriología , Línea Celular , Quinasa 5 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Electroforesis en Gel de Poliacrilamida , Glucógeno Sintasa Quinasa 3/metabolismo , Técnicas Histológicas , Inmunohistoquímica , Ratones , Ratones Mutantes , Proteínas Asociadas a Microtúbulos/fisiología , Factores de Crecimiento Nervioso/fisiología , Netrina-1 , Fosforilación , Proteínas Supresoras de TumorRESUMEN
During the development of the nervous system, neurons respond to the coordinated action of a variety of attractive and repulsive signals from the embryonic environment. Netrins form a family of extracellular proteins that regulate the migration of neurons and axonal growth cones. These proteins are bifunctional signals that are chemoattractive for some neurons and chemorepellent for others. Netrins mainly interact with the specific receptors DCC and UNC-5 family. To date, several Netrins have been described in mouse and humans: Netrin-1, -3/NTL2, -4/beta and G-Netrins. Netrin-1 is the most studied member of the family. It is involved in the development many projections of the nervous system. When Netrin-1 interacts with its specific receptors, a cascade of local cytoplasmic events is triggered. Several signal transduction pathways and effector molecules have been implicated in the response to Netrin-1: small Rho-GTPases, MAP-Kinases, second messengers and the Microtubule Associated Protein 1B (MAP1B).
Asunto(s)
Movimiento Celular/fisiología , Factores de Crecimiento Nervioso/fisiología , Sistema Nervioso/citología , Sistema Nervioso/embriología , Transducción de Señal/fisiología , Proteínas Supresoras de Tumor/fisiología , Animales , Humanos , Netrina-1 , Neuronas/citología , Neuronas/metabolismoRESUMEN
The signaling cascades governing neuronal migration are believed to link extracellular signals to cytoskeletal components. MAP1B is a neuron-specific microtubule-associated protein implicated in the control of the dynamic stability of microtubules and in the cross-talk between microtubules and actin filaments. Here we show that Reelin can induce mode I MAP1B phosphorylation, both in vivo and in vitro, through gsk3 and cdk5 activation. Additionally, mDab1 participates in the signaling cascade responsible for mode I MAP1B phosphorylation. Conversely, MAP1B-deficient mice display an abnormal structuring of the nervous system, especially in brain laminated areas, indicating a failure in neuronal migration. Therefore, we propose that Reelin can induce post-translational modifications on MAP1B that could correlate with its function in neuronal migration.