Final Report Summary - INTERMIG (Migration and integration of GABAergic interneurons into the developing cerebral cortex: a transgenic approach)
Cortical GABAergic interneurons represent the inhibitory neuronal component of the cortex. Their function is to modulate cortical excitability. Unlike the principal neurons of the cortex which are generated from endogenous cortical precursors, interneurons originate from subcortical germinal zones and migrate into the cortex during embryonic development. The aim of this project was to identify the sources of interneurons for the cortex as well as genetic pathways and signalling systems that underlie interneuron migration and integration into functional neuronal circuits.
Using genetic fate-mapping approaches in mice we comprehensively mapped the origins of cortical interneurons in the subcortical telencephalon. We adopted a novel genetic subtractive labeling approach to label interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) for which genetic markers were unknown. We demonstrated that the medial ganglionic eminence (MGE) and the LGE/CGE are the two major sources of interneurons for the cortex. Unlike previous suggestions, we demonstrated that the septum does not generate cortical interneurons. Our findings demonstrated that patterning of the embryonic subcortical neuroepithelium generates interneuron diversity in the adult cortex and that distinct neuroepithelial regions generate distinct interneurons that utilize the same migratory routes to reach the cortex. These findings reinforced the idea that cortical interneuron identity is determined at source. Using our genetic toolbox we extended our genetic fate-mapping studies into the adult subventricular zone where neurons are generated throughout life.
In order to identify genetic pathways that define interneurons according to their embryonic origin, we have used our transgenic toolbox to genetically tag and purify different cohorts of interneurons. We have examined their transcriptome by microarray analysis and have defined their distinct molecular signature. We identified the transcription factor PROX1 as a novel lineage tracer of a large subset of cortical interneurons. PROX1 provides a novel tool for identifying these cells in the cortex and raises questions about the role of this transcription factor in cortical interneuron development. We expanded our analysis into other differentially expressed transcription factors and synaptogenic molecules in order to obtain a more complete genetic make-up of the two major interneuron cohorts of the cortex.
Using genetic fate-mapping approaches in mice we comprehensively mapped the origins of cortical interneurons in the subcortical telencephalon. We adopted a novel genetic subtractive labeling approach to label interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) for which genetic markers were unknown. We demonstrated that the medial ganglionic eminence (MGE) and the LGE/CGE are the two major sources of interneurons for the cortex. Unlike previous suggestions, we demonstrated that the septum does not generate cortical interneurons. Our findings demonstrated that patterning of the embryonic subcortical neuroepithelium generates interneuron diversity in the adult cortex and that distinct neuroepithelial regions generate distinct interneurons that utilize the same migratory routes to reach the cortex. These findings reinforced the idea that cortical interneuron identity is determined at source. Using our genetic toolbox we extended our genetic fate-mapping studies into the adult subventricular zone where neurons are generated throughout life.
In order to identify genetic pathways that define interneurons according to their embryonic origin, we have used our transgenic toolbox to genetically tag and purify different cohorts of interneurons. We have examined their transcriptome by microarray analysis and have defined their distinct molecular signature. We identified the transcription factor PROX1 as a novel lineage tracer of a large subset of cortical interneurons. PROX1 provides a novel tool for identifying these cells in the cortex and raises questions about the role of this transcription factor in cortical interneuron development. We expanded our analysis into other differentially expressed transcription factors and synaptogenic molecules in order to obtain a more complete genetic make-up of the two major interneuron cohorts of the cortex.