EMX2 Regulates Sizes and Positioning of the Primary Sensory and Motor Areas in Neocortex by Direct Specification of Cortical Progenitors

Hamasaki, Tadashi; Leingärtner, Axel; Ringstedt, Thomas; O’Leary, Dennis D.M.

doi:10.1016/j.neuron.2004.07.016

Cited by 214 publications

(231 citation statements)

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“…Our analyses additionally reveal that all primary sensory areas are present, but suggest that the regulation of specific levels of Foxg1 expression may be a key modulator of the relative size of functional areas in the cerebral cortex in the tangential domain. A similar dependence has been reported for Emx2, where the size of primary sensory and motor areas was influenced by altered levels of the transcription factor (Hamasaki et al, 2004). The suggestion that Foxg1 may reduce Emx2 expression levels (Muzio and Mallamaci, 2005) is consistent with our finding in the Foxg1 haploinsufficent mouse of a disproportionate increase in V1 and decrease in PMSBF, similar to the phenotype observed when Emx2 is overexpressed in cortical progenitors.…”

Section: Foxg1 Haploinsufficiency and Cortical Developmentsupporting

confidence: 89%

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

et al. 2007

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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...

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Section: Foxg1 Haploinsufficiency and Cortical Developmentsupporting

confidence: 89%

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

et al. 2007

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“…The concentration of Emx2 is highest in posterior and medial regions, and lowest in anterior lateral regions; Pax6 has the opposite expression pattern. The interaction of these two gradients contributes to early patterning of the neocortex (Bishop et al 2002;Hamasaki et al 2004). High concentrations of Pax6 combined with low Emx2 induces progenitors to produce neurons appropriate for motor cortex (M1), while the reverse concentrations induce production of neurons for visual cortex (V1).…”

Section: Neural Patterning In the Embryonic Periodmentioning

confidence: 99%

The Basics of Brain Development

Stiles¹,

Reilly²,

Levine³

et al. 2012

Neural Plasticity and Cognitive Development

134

150

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“…Establishing a relationship between area size and behavioral performance could be predictive for behavioral differences between individuals and provide insight into the functional importance of cortical areas (2). These relationships could also provide insights into developmental cognitive disorders (10) and the potential for aberrant behavior due to polymorphisms that influence the expression of regulatory genes that control area patterning (11).Area size is controlled in part by transcription factors, including the homeodomain protein EMX2 expressed by cortical progenitors, that specify during embryonic development the area identities of cortical progenitors and their neuronal progeny (12)(13)(14). Analyses of nestin-Emx2 transgenic (ne-Emx2) mice and heterozygous Emx2 knockout (Emx2ϩ/Ϫ) mice, which have increased or decreased levels of Emx2 expression in cortical progenitors, respectively, show opposing changes in sizes of S1 and motor areas in mature mice (14).…”

mentioning

confidence: 99%

“…Area size is controlled in part by transcription factors, including the homeodomain protein EMX2 expressed by cortical progenitors, that specify during embryonic development the area identities of cortical progenitors and their neuronal progeny (12)(13)(14). Analyses of nestin-Emx2 transgenic (ne-Emx2) mice and heterozygous Emx2 knockout (Emx2ϩ/Ϫ) mice, which have increased or decreased levels of Emx2 expression in cortical progenitors, respectively, show opposing changes in sizes of S1 and motor areas in mature mice (14).…”

mentioning

confidence: 99%

“…Analyses of nestin-Emx2 transgenic (ne-Emx2) mice and heterozygous Emx2 knockout (Emx2ϩ/Ϫ) mice, which have increased or decreased levels of Emx2 expression in cortical progenitors, respectively, show opposing changes in sizes of S1 and motor areas in mature mice (14). For example, in ne-Emx2 mice, increasing Emx2 expression in cortical progenitors by driving an Emx2 transgene under control of a neuron-specific nestin promoter results in a significant decrease in sizes of sensorimotor areas but has no effect on overall cortical size or lamination.…”

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confidence: 99%

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Cortical area size dictates performance at modality-specific behaviors

Leingärtner

Thuret

Kroll

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian neocortex is organized into unique areas that serve functions such as sensory perception and modality-specific behaviors. The sizes of primary cortical areas vary across species, and also within a species, raising the question of whether area size dictates behavioral performance. We show that adult mice genetically engineered to overexpress the transcription factor EMX2 in embryonic cortical progenitor cells, resulting in reductions in sizes of somatosensory and motor areas, exhibit significant deficiencies at tactile and motor behaviors. Even increasing the size of sensorimotor areas by decreasing cortical EMX2 levels can lead to diminished sensorimotor behaviors. Genetic crosses that retain ectopic Emx2 transgene expression subcortically but restore cortical Emx2 expression to wild-type levels also restore cortical areas to wild-type sizes and in parallel restore tactile and motor behaviors to wild-type performance. These findings show that area size can dictate performance at modality-specific behaviors and suggest that areas have an optimal size, influenced by parameters of its neural system, for maximum behavioral performance. This study underscores the importance of establishing during embryonic development appropriate levels of regulatory proteins that determine area sizes, thereby influencing behavior later in life.cortex ͉ EMX2 ͉ sensorimotor performance ͉ cortical area patterning ͉ somatosensory cortex T he mammalian neocortex is tangentially organized into areas that serve unique functions such as sensory perception and modality-specific behaviors. In humans, the primary areas, motor (M1), somatosensory (S1), and visual (V1), vary Ϸ2-fold in size in a smooth continuum (1-5). In mice, the sizes of V1 and the S1 barrelfield are very consistent within inbred strains of mice, but their mean sizes can differ between some inbred strains of mice (6).These observations raise the question of whether the size of a cortical area influences behavioral performance. Normal humans exhibit significant differences in proficiency at visual psychophysical tasks (7), but these differences have not been correlated to differences in area size. Complementing these findings are studies of adult cortical plasticity. For example, repetitive use of a digit, or microstimulation of its cortical representation, results in an enlarged functional representation in M1 and S1 resulting in an increased overlap with functional representations of adjacent digits. These enlargements, which are evident physiologically but not anatomically, do not extend across area borders, do not increase area size, and have not been shown to affect systems-level behavior (8, 9).Here we address whether differences in cortical area size influence modality-specific behaviors in adults by using genetic manipulations that act during embryonic development to alter cortical area size in a consistent, reproducible manner. Establishing a relationship between area size and behavioral performance could be predictive for behavioral differences between ...

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EMX2 Regulates Sizes and Positioning of the Primary Sensory and Motor Areas in Neocortex by Direct Specification of Cortical Progenitors

Cited by 214 publications

References 50 publications

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

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

The Basics of Brain Development

Cortical area size dictates performance at modality-specific behaviors

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