[P141]: Foxg1 haploinsufficiency disrupts radial and tangential neocortical development

Mammalian corticogenesis relies on the sequential activation of specific transcriptional events for the appropriate production and differentiation of neurons expressing discrete laminar and regional fates. Homozygous deletion of the transcription repressor, Foxg1, results in unregulated cortical progenitor cell division and differentiation, while Foxg1 heterozygous mice, on a mixed background strain, are reported to be normal. However, we have identified disrupted forebrain development in a congenic C57Bl/6 strain of the Foxg1-Cre mouse, in which the level of Foxg1 message is half that in wild type littermates. Using magnetic resonance microscopy, we demonstrate that the volume of the adult male brain is reduced by 30%, including diverse reductions in neocortical (40%), hippocampal (17%) and striatal (28%) volumes. With respect to the cortex, both the radial and tangential dimensions are affected. In the radial domain, the supragranular and granular layers are significantly thinner, with a corresponding reduction in the corpus callosum. In contrast, the infragranular layers are normal. Immunocytochemical and in situ hybridization analyses of embryonic and early postnatal cortices suggest that this phenotype is due, at least in part, to an incomplete production of neurons destined for layers II–IV. Interestingly, although the tangential extent of the cortex is 30% smaller than wild type, patterning of this structure appears essentially normal. Thus, primary sensory areas, identified by SERT immunoreactivity at P8 and cytochrome oxidase in the adult, are proportionally smaller and occupy the same relative location within the cortical sheet. Surprisingly, although Foxg1 is not expressed in the thalamus, the volume of this structure is reduced by 20% in the adult. We hypothesize that this is due to a smaller thalamic target field in the cortex and, perhaps, reduced cortico-thalamic feedback. Taken together, these results suggest that control of Foxg1 expression levels is important for defining the composition of cells in the cerebral cortex. Moreover, while the patterning and initial organization of the cerebral cortex and dorsal thalamus are independently regulated, postnatal compensatory mechanisms appear to be essential for producing a well-organized topographic map. Finally, the genetic background can influence significantly the impact of dysregulated levels of transcription factors on forebrain development.