RESUMEN
The molecular mechanisms that activate morphogenesis of cerebral cortex are currently the subject of intensive experimental analysis. Transcription factor genes of the homeobox, basic helix-loop-helix (bHLH) and zinc-finger families have recently been shown to have essential roles in this process. However, the actual selector genes activating corticogenesis have not yet been identified. Here we show that high-level expression of at least one functional allele of either of the homeobox genes Emx2 or Pax6 in the dorsal telencephalon is necessary and sufficient to stably activate morphogenesis of cerebral cortex and to repress that of adjacent structures, such as striatum.
Asunto(s)
Ganglios Basales/anomalías , Corteza Cerebral/anomalías , Proteínas de Homeodominio/metabolismo , Malformaciones del Sistema Nervioso/embriología , Alelos , Animales , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/genética , Ganglios Basales/metabolismo , Ganglios Basales/patología , Diferenciación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Regulación hacia Abajo , Proteínas del Ojo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Noqueados , Ratones Mutantes , Morfogénesis , Malformaciones del Sistema Nervioso/metabolismo , Malformaciones del Sistema Nervioso/patología , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Proteínas Represoras , Células Madre/citología , Factores de TranscripciónRESUMEN
It has recently been demonstrated that the transcription factor genes Emx2 and Pax6, expressed in the developing cerebral cortex along two complementary tangential gradients, are essential for the shaping of the cortical areal profile at late developmental ages, when cortical neuronogenesis is almost completed. In this study we addressed the question of whether cortical regionalization is already affected in Emx2 and Pax6 loss of function mutants at the beginning of neuronogenesis. By comparing expression patterns of selected molecular markers in these mutants at this age, we found that: (i) Emx2 and Pax6 are necessary for the establishment of their own specific expression profiles and are able to down-regulate each other; and (ii) absence of functional EMX2 or PAX6 proteins results in reduction of caudal-medial and rostral-lateral cortical regions, respectively, as well as in impairment of the WNT signalling center at the medial-caudal edge of the cortical field, crucial for cortical growth. These results suggest that pre-neuronogenic cortical regionalization may rely on mutual interactions between these two transcription factors and that the late areal phenotype of Emx2(-/-) and Pax6(-/-) mutants may possibly arise from both misconfiguration of the cortical molecular protomap and distortion of the cortical growth profile.