RESUMEN
First insights into the molecular programs orchestrating the progression from neural stem cells to cortical projection neurons are emerging. Loss of the transcriptional regulator Ski has been linked to the human 1p36 deletion syndrome, which includes central nervous system defects. Here, we report critical roles for Ski in the maintenance of the neural stem cell pool and the specification of callosal neurons. Ski-deficient callosal neurons lose their identity and ectopically express the transcription factor Ctip2. The misspecified callosal neurons largely fail to form the corpus callosum and instead redirect their axons toward subcortical targets. We identify the chromatin-remodeling factor Satb2 as a partner of Ski, and show that both proteins are required for transcriptional repression of Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski to the Ctip2 locus, and Ski attracts histone deacetylases, thereby enabling the formation of a functional nucleosome remodeling and deacetylase repressor complex. Our findings establish a central role for Ski-Satb2 interactions in regulating transcriptional mechanisms of callosal neuron specification.
Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Cuerpo Calloso/citología , Proteínas de Unión al ADN/fisiología , Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Proteínas del Tejido Nervioso/fisiología , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Proteínas Represoras/biosíntesis , Factores de Transcripción/fisiología , Proteínas Supresoras de Tumor/biosíntesis , Agenesia del Cuerpo Calloso/embriología , Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Animales , Axones/ultraestructura , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Histona Desacetilasas/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/deficiencia , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Ratones , Ratones Noqueados , Ratones Mutantes Neurológicos , Modelos Genéticos , Complejos Multiproteicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neurogénesis/genética , Nucleosomas/metabolismo , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
The assembly of neuronal networks during development requires tightly controlled cell-cell interactions. Multiple cell surface receptors that control axon guidance and synapse maturation have been identified. However, the signaling mechanisms downstream of these receptors have remained unclear. Receptor signals might be transmitted through dedicated signaling lines defined by specific effector proteins. Alternatively, a single cell surface receptor might couple to multiple effectors with overlapping functions. We identified the neuronal RacGAP alpha2-chimaerin as an effector for the receptor tyrosine kinase EphA4. alpha2-Chimaerin interacts with activated EphA4 and is required for ephrin-induced growth cone collapse in cortical neurons. alpha2-Chimaerin mutant mice exhibit a rabbit-like hopping gait with synchronous hindlimb movements that phenocopies mice lacking EphA4 kinase activity. Anatomical and functional analyses of corticospinal and spinal interneuron projections reveal that loss of alpha2-chimaerin results in impairment of EphA4 signaling in vivo. These findings identify alpha2-chimaerin as an indispensable effector for EphA4 in cortical and spinal motor circuits.
Asunto(s)
Sistema Nervioso Central/anomalías , Sistema Nervioso Central/metabolismo , Quimerina 1/fisiología , Vías Nerviosas/anomalías , Vías Nerviosas/metabolismo , Receptor EphA4/metabolismo , Animales , Comunicación Celular/genética , Diferenciación Celular/genética , Sistema Nervioso Central/fisiopatología , Corteza Cerebral/anomalías , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Quimerina 1/genética , Quimerina 1/metabolismo , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/metabolismo , Trastornos Neurológicos de la Marcha/fisiopatología , Regulación del Desarrollo de la Expresión Génica/genética , Conos de Crecimiento/metabolismo , Conos de Crecimiento/ultraestructura , Miembro Posterior/inervación , Miembro Posterior/fisiopatología , Ratones , Ratones Mutantes , Vías Nerviosas/fisiopatología , Fenotipo , Tractos Piramidales/anomalías , Tractos Piramidales/metabolismo , Tractos Piramidales/fisiopatología , Médula Espinal/anomalías , Médula Espinal/metabolismo , Médula Espinal/fisiopatologíaRESUMEN
Structure and function of presynaptic terminals are critical for the transmission and processing of neuronal signals. Trans-synaptic signaling systems instruct the differentiation and function of presynaptic release sites, but their downstream mediators are only beginning to be understood. Here, we identify the intracellular mSYD1A (mouse Synapse-Defective-1A) as a regulator of presynaptic function in mice. mSYD1A forms a complex with presynaptic receptor tyrosine phosphatases and controls tethering of synaptic vesicles at synapses. mSYD1A function relies on an intrinsically disordered domain that interacts with multiple structurally unrelated binding partners, including the active zone protein liprin-α2 and nsec1/munc18-1. In mSYD1A knockout mice, synapses assemble in normal numbers but there is a significant reduction in synaptic vesicle docking at the active zone and an impairment of synaptic transmission. Thus, mSYD1A is a regulator of presynaptic release sites at central synapses.