EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

Abstract

Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

“…[50][51][52] Analyses of the size of the cortex of these mice at postnatal day 10, 15, 25, and 110 demonstrate that conditional knockout of Nfib in Cre-positive mice (cKO) resulted in a significant increase in cortical length and width (medio-lateral size) compared to their Cre-negative littermates (WT) at all ages ( Figure 4B; one-way ANOVA). To further determine whether Nfib deletion altered the overall structure of the cortex, fast low-angle shot (FLASH; Figure S2) and diffusion-weighted spin-echo magnetic resonance imaging (dMRI; Figures 4C and 4D) 54,55 as well as histological analyses ( Figures 4G and 4H) were performed. No major structural changes were observed in the brain.…”

“…Probabilistic tractography was performed to detect cortical connectivity and topographic organization of the corpus callosum. 54,55 The structural MR image for each mouse brain was divided into 20 segments via the multi-atlas segmentation tool provided by Advanced Normalization Tools (v 2.2.0, stnava). Nine hand parcellated mouse brain atlases from the Magnetic Resonance Microimaging Neurological Atlas formed the basis of the multi-atlas segmentation.…”

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

“…EMX1 deletion in mice results in a smaller hippocampus and a lack of the corpus callosum ( Qiu et al, 1996 ). In addition, Lim et al (2015) showed that EMX1 functions in “cingulate callosal axon guidance” by regulating the expression of NRP1 , which in turn, was also identified as differentially methylated in the EtG+ group. Differentially methylated are also several genes coding for the proteins of the voltage-gated potassium channels.…”

Deciphering the Role of Emx1 in Neurogenesis: A Neuroproteomics Approach

“…Existing literature suggests that the Emx1 transcription factor is not among the most critical players in mammalian brain development since the Emx1 -single mutant was not only viable but also without any severe CNS phenotype in contrast to the mutations caused by a number of other genes (Patarnello et al, 1997 ; Guo et al, 2000 ; Bishop et al, 2002 , 2003 ; Cao and Li, 2002 ; Muzio and Mallamaci, 2003 ; Shinozaki et al, 2004 ; Tamamaki, 2005 ; von Frowein et al, 2006 ; Piper et al, 2007 ; Cocas et al, 2009 ; Sen et al, 2013 ). The role of Emx1 during brain development was first implicated in axon guidance, regulating midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex (Lim et al, 2015 ). Apart from an acallosal phenotype, the adult Emx1 null mice also exhibited smaller dentate gyri and reduced neurogenesis (Hong et al, 2007 ).…”