Molecular regulation of the developing commissural plate

Abstract

Coordinated transfer of information between the brain hemispheres is essential for function and occurs via three axonal commissures in the telencephalon: the corpus callosum (CC), hippocampal commissure (HC) and anterior commissure (AC). Commissural malformations occur in over 50 human congenital syndromes causing mild to severe cognitive impairment. Disruption of multiple commissures in some syndromes suggests that common mechanisms may underpin their development. Diffusion tensor magnetic resonance imaging revealed that forebrain commissures crossed the midline in a highly specific manner within an oblique plane of tissue, referred to as the commissural plate. This specific anatomical positioning suggests that correct patterning of the commissural plate may influence forebrain commissure formation. No analysis of the molecular specification of the commissural plate has been performed in any species, therefore we utilized specific transcription factor markers to delineate the commissural plate, and identify its various sub-domains. We found that the mouse commissural plate consists of four domains, and tested the hypothesis that disruption of these domains might affect commissure formation. Disruption of the dorsal domains occurred in strains with commissural defects such as Emx2 and Nfia knockout mice but commissural plate patterning was normal in other acallosal strains such as Satb2. Finally, we demonstrate an essential role for the morphogen, Fgf8 in establishing the commissural plate at later developmental stages. The results demonstrate that correct patterning of the commissural plate is an important mechanism in forebrain commissure formation.

Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum

“…Previously we have shown that the expression of the morphogen Fgf8 within the septal midline is critical for the tissue patterning of this region (Moldrich et al, 2010; Storm et al, 2006). We therefore investigated whether Fgf8 may also regulate later aspects of septal midline development such as interhemispheric midline remodeling.…”

“…To examine the functional consequence of reducing Fgf8 expression on interhemispheric remodeling, we analyzed the development of conditional Fgf8 flox /Emx1 Cre mutants, which exhibit loss of Fgf8 in the pallium and pallial derivatives of the septum from E10.5 (Figures 4C and S3; Moldrich et al, 2010). Homozygous Fgf8 flox /Emx1 Cre -positive (Fgf8cKO) mutants display moderate to severe midline defects compared to controls.…”

“…Homozygous Fgf8 flox /Emx1 Cre -positive (Fgf8cKO) mutants display moderate to severe midline defects compared to controls. While the septum is present in moderate Fgf8cKO mutants (14/25 analyzed), it is completely absent in severe Fgf8cKO mutants (11/25 analyzed), resulting in semilobar holoprosencephaly with communicating lateral ventricles (Figures 4C and S3; Moldrich et al, 2010). Notably, IHF remodeling failed to occur in either moderate or severe Fgf8cKO mutants, resulting in abnormal retention of the IHF and agenesis of the corpus callosum and hippocampal commissure in both mutant types (Figures 4C and 4D).…”

“…Brain sections were processed for either chromogenic immunohistochemistry or standard fluorescence immunohistochemistry as previously described (Moldrich et al, 2010) with minor modifications. With the exception of MMPSense-treated tissue, all sections were post-fixed in 4% paraformaldehyde, and subjected to antigen retrieval (125°C for 4 minutes at 15 psi in sodium citrate buffer) prior to incubation with primary antibodies.…”

Evolution and development of interhemispheric connections in the vertebrate forebrain

“…Thus, the specific location through which commissural axons cross the midline depends on the early molecular patterning of the commissural plate, whereby pioneer axons of the corpus callosum cross through the same pallial domain of the dorsal hippocampal commissure, while the ventral hippocampal and anterior commissures form at the septal and preoptic domains, respectively (Figure 4F; Moldrich et al, 2010). Taken together, comparative and molecular data suggest that evolution of the corpus callosum involved a rerouting of commissural axons through a preexistent pallial commissural course.…”