The cortical hem regulates the size and patterning of neocortex

Abstract

The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in latestage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.

Akirin2 is essential for the formation of the cerebral cortex

“…Cortical size and patterning depends upon Wnts secreted by the medially-situated cortical hem [34]. We thus asked whether the hem (in which the Emx1-Cre transgene is active; [25, 34]) might be disrupted in the absence of Akirin2 .…”

“…We thus asked whether the hem (in which the Emx1-Cre transgene is active; [25, 34]) might be disrupted in the absence of Akirin2 . In situ hybridization suggested that this, indeed, was the case, as strong expression of hem markers Wnt3a (E10.5 and E11, Fig.…”

Regulation of Wnt signaling by protocadherins

“…Our data suggest a novel mechanism in which the interaction of γ-Pcdh-C3 with Axin1 can potentially sequester it away from other Wnt signaling components, which leads to Lrp6 hypophosphorylation and reduced Wnt target gene expression through an as-yet undetermined pathway. It is likely that γ-Pcdhs act as modulators or buffers for Wnt signaling activity, rather than as primary co-factors, as a grossly normal cerebral cortex still forms in mice overexpressing γ-Pcdh-C3 or –A1 [204]; major disruption of Wnt signaling in embryonic telencephalon (e.g., through ablation of the Wnt-producing cortical hem; [205]) leads to a severe disruption of cortical development. As it stands, it will be important to determine if any of the many roles that γ-Pcdhs play in the brain are dependent on its modulation of Wnt pathways.…”

The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

“…The cortical hem is the embryonic organizer for the hippocampus and a major regulator of cortical patterning outside the hippocampus. It provides a source of Winglessrelated (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon to control proper cortical regionalization and NPC expansion in a paracrine fashion (15,16). Thus, the severe patterning and arealization defects in Dmrta2-null model organisms prohibit a clear dissection of a direct role of Dmrta2 in NPC behavior from the secondary effect of an overall reduction in extrinsic hem-derived signals.…”