Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon

Abstract

During forebrain development, a telencephalic organizer called the cortical hem is crucial for inducing hippocampal fate in adjacent cortical neuroepithelium. How the hem is restricted to its medial position is therefore a fundamental patterning issue. Here, we demonstrate that Foxg1-Lhx2 interactions are crucial for the formation of the hem. Loss of either gene causes a region of the cortical neuroepithelium to transform into hem. We show that FOXG1 regulates Lhx2 expression in the cortical primordium. In the absence of Foxg1, the presence of Lhx2 is sufficient to suppress hem fate, and hippocampal markers appear selectively in Lhx2-expressing regions. FOXG1 also restricts the temporal window in which loss of Lhx2 results in a transformation of cortical primordium into hem. Therefore, Foxg1 and Lhx2 form a genetic hierarchy in the spatiotemporal regulation of cortical hem specification and positioning, and together ensure the normal development of this hippocampal organizer.

Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex

“…2e, Extended Data Fig. 1); this pattern precisely recapitulates the endogenous Lhx2 expression 26,27 . These early RGs showed characteristic radial fibers and end-feet at the ventricle surface; the position of their soma likely reflected the stage of cell cycle progression, including those dividing at the ventricle surface ( Fig.…”

Forced Expression of Foxg1 in the Cortical Hem Leads to the Transformation of Cajal-Retzius Cells into Dentate Granule Neurons

“…Here, by overexpression of Foxg1 in the hem from E10.5 onwards, we detected a cell fate switch of the hem-derived CR cells to dentate granule neurons, accompanied with ectopic expression of Lhx2. Previous study has reported that loss of Foxg1 leads to a reduction of Lhx2 expression, and Foxg1 can directly bind to Lhx2 locus [ 16 ]. In this study, we demonstrated that forced expression of Foxg1 is sufficient to induce Lhx2 expression in the hem.…”

“…In this study, we demonstrated that forced expression of Foxg1 is sufficient to induce Lhx2 expression in the hem. It has been reported that Lhx2-expressing cells can be specified into hippocampal cells and this only happens in tissues adjacent to the hem [ 16 ]. Here, induced expression of Lhx2 in our transgenic mice may be responsible for the transformation of CR cells to their granular fate.…”

“…Early constitutive loss of Foxg1 (around E8.5–9.0) results in severe expansion of the hem, while removal of Foxg1 at E13.5 has no obvious influences [ 13 , 16 ], suggesting that Foxg1 may regulate the hem in a spatiotemporal manner. In this study, Foxg1 was forced to be expressed in the hem from E10.5 onwards.…”

“…Both Foxg1 and Lhx2 null mutants exhibit significant expansion of the hem [ 14 , 15 ]. Recently, Godbole and colleagues showed that Foxg1 functions upstream of Lhx2 to regulate the specification and positioning of the hem, providing new insight into the mechanisms regulating the hem formation [ 16 ]. On the other hand, there are obvious phenotype differences between Foxg1 and Lhx2 knockouts.…”