Emx2 in the developing hippocampal fissure region

Abstract

Mice deficient in transcription factor gene Emx2 show developmental alterations in the hippocampal dentate gyrus. Emx2, however, is also expressed in the region around the developing hippocampal fissure. The developing fissure contains a radial glial scaffolding, and is surrounded by the outer marginal zone and the dentate marginal zone, which become specifically colonized by neurons and differentiate into stratum lacunosum-moleculare and molecular layer of the dentate, respectively. In this study we show that the Emx2 mutant lacks the glial scaffolding of the fissure and has an outer marginal zone (precursor of the stratum lacunosum-moleculare), as well as a dentate marginal zone severely reduced in size while most of the reelin (Reln)-expressing cells that should occupy it fail to be generated. We have also identified a subpopulation of hippocampal Reln-expressing cells of the marginal zone, probably born in the hem, expressing a specific combination of markers, and for which Emx2 is not essentially required. Additionally, we show differential mutant phenotypes of both Emx2 and Pax6 in neocortical vs. hippocampal Reln-expressing cells, indicating differential development of both subpopulations.

Specific Glial Populations Regulate Hippocampal Morphogenesis

“…Especially prominent during the development of this region is the involvement of radial glia. Only a small number of factors have been identified that may be involved in the formation of the GFAP-positive glial scaffold during hippocampal development (Oldekamp et al, 2004;Zhou et al, 2004;Zhao et al, 2006). Here, we demonstrate that the maturation of distinct populations of radial glia are critical for certain aspects of DG formation, particularly the emergence of the hippocampal fissure and the migration of dentate granule cells.…”

“…Foxg1, expressed very early in the telencephalon, most likely regulates cell fate upstream or independent of Nfib, as we did not detect any abnormality of the cortical hem of Nfib-deficient mice. Mice deficient in the transcription factors Emx2 and Pax6 have a similar hippocampal phenotype to the Nfib-deficient mice (Pellegrini et al, 1996;Tole et al, 2000;Oldekamp et al, 2004;Zhao et al, 2006). For instance, each mutant lacks a discernible hippocampal fissure.…”

“…For instance, each mutant lacks a discernible hippocampal fissure. Furthermore, Emx2 mutants display impaired GFAP expression and have defective Prox1-positive granule cell migration (Oldekamp et al, 2004;Zhao et al, 2006). As Emx2 is expressed earlier than Nfib in the mouse brain (Simeone et al, 1992) it may be that Nfib is a downstream target of Emx2.…”

“…Both the supragranular glial bundle, and the fimbrial glial bundle express GFAP but it is not known whether these glia are derived from similar or distinct progenitors, or how their development is molecularly regulated. Recent work has implicated the transcription factor Emx2 in hippocampal morphogenesis (Oldekamp et al, 2004;Zhao et al, 2006;Skutella et al, 2007), as hippocampal expression of GFAP is reduced at E18.5 in these mutants. However, these studies did not address either earlier glial development, or the importance of glial maturation to hippocampal development.…”

Nuclear factor I gene expression in the developing forebrain

“…Importantly, Nfib knockout mice display hippocampal defects, including malformation of the dentate gyrus (SteelePerkins et al, 2005). A similar hippocampal phenotype has been observed in Emx2 knockout mice (Tole et al, 2000;Zhao et al, 2006), and microarray analysis in neural precursors identified Nfia as a downstream target of Emx2 (Gangemi et al, 2006). Another mouse mutant with similar hippocampal abnormalities is the LRP6 (low-density lipoprotein receptor-related protein)-deficient mice.…”