Disruption of Foxg1 expression by knock-in of Cre recombinase: Effects on the development of the mouse telencephalon

Abstract

The Cre/loxP system is used routinely to manipulate gene expression in the mouse nervous system. In order to delete genes specifically from the telencephalon, the Foxg1-cre line was created previously by replacing the intron-less Foxg1 coding region with cre, resulting in a Foxg1 heterozygous mouse. As the telencephalon of heterozygous Foxg1 mice was reported to be normal, this genotype often has been used as the control in subsequent analyses. Here we describe substantial disruption of forebrain development of heterozygous mice in the Foxg1-cre line, maintained on the C57BL/6J background. High resolution magnetic resonance microscopy reveals a significant reduction in the volume of the neocortex, hippocampus and striatum. The alteration in the neocortex results, in part, from a decrease in its tangential dimension, although gross patterning of the cortical sheet appears normal. This decrease is observed in three different Foxg1 heterozygous mouse lines, independent of the method of achieving deletion of the Foxg1 gene. Although Foxg1 is not expressed in the diencephalon, three-dimensional magnetic resonance microscopy revealed that thalamic volume in the adult is reduced. In contrast, at postnatal day 4, thalamic volume is normal, suggesting that interactions between cortex and dorsal thalamus postnatally produce the final adult thalamic phenotype. In the Foxg1-cre line maintained on the C57BL/6J background, the radial domain of the cerebral cortex also is disrupted substantially, particularly in supragranular layers. However, neither Foxg1 heterozygous mice of the Foxg1-tet line, nor those of the Foxg1-lacZ and Foxg1-cre lines maintained on a mixed background, displayed a reduced cortical thickness. Thus Cre recombinase contributes to the radial phenotype, although only in the context of the congenic C57BL/6J background. These observations highlight an important role for Foxg1 in cortical development, reveal noteworthy complexity in the invocation of specific mechanisms underlying phenotypes expressed following genetic manipulations and stress the importance of including appropriate controls of all genotypes. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Development of the cerebral cortex relies on extracellular cues and intrinsic signals that instruct the proliferation, differentiation and migration of neuronal precursors. The duration and location of these cues are critical to producing the final cortical architecture (FukuchiShimogori and Grove, 2001, Parnavelas et al., 2002, Rakic, 2002, Shimogori et al., 2004, Rash and Grove, 2006, Storm et al., 2006. The...

HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain

“…This is possibly due to the different expression patterns of Foxg1 and Hesx1, or is a potential additive effect due to Foxg1 haploinsufficiency in the Foxg1-Cre knock-in line used, as even heterozygous animals have telencephalic defects (Eagleson et al, 2007).…”

JNK regulates FoxO-dependent autophagy in neurons

“…B6.129-Tg(Pcp2-cre)2Mpin/J mice (Barski et al 2000), B6.CgTg(Nes-cre)1Kln/J mice (Tronche et al 1999), and B6.129P2(Cg)-Foxg1 tm1(cre)Skm /J mice (Eagleson et al 2007) were obtained from The Jackson Laboratories. These mice were backcrossed to the C57BL/6J strain (Jackson Laboratories) and were housed in a facility accredited by the American Association for Laboratory Animal Care.…”

Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP

“…By E13.5, reporter expression was found throughout the otic lines are used. The most commonly used line is the depending on the strength of the fluorescent reporter COX ET.AL: Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP Pirvola et al 2002;Arnold et al 2006;Zelarayan et al 2007;Barrionuevo et al 2008;Jones et al 2008;Rickheit et al 2008;Grimsley-Myers et al 2009;Schultz et al 2009;Wang et al 2009;Yamamoto et al 2009;Deng et al 2010;Freyer and Morrow 2010;Haugas et al 2010;Hurd et al 2010;Hwang et al 2010;Sipe and Lu 2011 (Hebert and McConnell 2000), which has been reported to cause haploinsufficiency phenotypes that include proliferation in other organs (Shen et al 2006;Eagleson et al 2007;Siegenthaler et al 2008). However, no change in proliferation in the inner ear has been reported in several papers where proper controls of Foxg1-Cre mice (without the floxed allele) were used (Yamamoto et al 2009(Yamamoto et al , 2011Hartman et al 2010;Brown and Epstein 2011).…”