Early Asymmetry of Gene Transcription in Embryonic Human Left and Right Cerebral Cortex

Abstract

The human left and right cerebral hemispheres are anatomically and functionally asymmetric. To test whether human cortical asymmetry has a molecular basis, we studied gene expression levels between the left and right embryonic hemispheres using Serial Analysis of Gene Expression (SAGE), and identified and verified 27 differentially expressed genes, suggesting that human cortical asymmetry is accompanied by early, striking transcriptional asymmetries. LMO4 is consistently more highly expressed in the right perisylvian human cerebral cortex than in the left, and is essential for cortical development in mice, suggesting that human left-right specialization reflects asymmetric cortical development at early stages.One of the most remarkable aspects of the human cerebral cortex is that the two hemispheres are specialized for distinct cognitive and behavioral functions. Whereas the right cerebral cortex regulates movement of the left side of the body and vice versa, approximately 90% of the human population is naturally more skilled with the right hand than with the left (1). This motor asymmetry is strongly correlated with language dominance: language function is predominantly localized to a distributed network in the left perisylvian cortex in 97% of righthanders and about 60% of left-handers (2,3). Functional asymmetries exist in mathematical ability, and spatial and facial recognition as well. These functional asymmetries have been related to anatomical asymmetries of the cortex that are somewhat more subtle (2,4). For example, the posterior end of the Sylvian fissure, is higher in the right hemisphere than in the left (5). The planum temporale, a region in the posterior portion of the superior temporal sulcus in which Wernike's area resides, is larger in the left than in the right in more than 65% of examined adult and 56-79% of fetuses or infant brains, so that the anatomical asymmetries are less striking than the functional ones (6,7). Although genetic factors connecting cerebral Here we directly tested the hypothesis that left-right cortical asymmetry in humans results from differential gene expression at early embryonic stages, long before the onset of organized cerebral cortical function. By applying Serial Analysis of Gene Expression (SAGE), we measured gene expression levels between the left and right hemispheres in early (12-14 weeks) embryonic human brains, during periods of neuronal proliferation and migration, and later (19 weeks), after these processes are largely completed (9). Brain tissues were first dissected from matching perisylvian regions in two hemispheres (Fig. 1, A to C). The cortex was then separated at the midline. On the medial side of the hemisphere, tissues were also dissected from the ventricular zone in the frontal and occipital regions (Fig. 1B). Total RNA was isolated and 14 SAGE libraries were generated (Fig. 1D). To detect genes with differential expression levels, we compared tag frequency for each gene between two SAGE libraries generated from the frontal, perisylvian an...

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence

“…Increased heritability over childhood and adolescence has been observed in cognitive traits such as IQ and prosocial behavior [Knafo and Plomin, 2006]. One likely contributor to changing heritability is agedependent gene expression Sun et al, 2005;Weickert et al, 2007]. Another potential factor is gene-environment correlation, which occurs when the same genes affect both a trait and relevant features of the environment, and also acts to increase heritability values [Kendler and Baker, 2007;Scarr and McCartney, 1983].…”

“…Hulshoff Pol et al [2006] found evidence for significant heritability of gray and white matter density within several brain regions in a twin study of 258 adult subjects. There have been no previous studies of developmental changes in heritability of cortical features in humans, despite evidence of developmental changes in postnatal cortical structure [Gogtay et al, 2004] and postnatal gene expression [Plomin and Craig, 1997;Sun et al, 2005].…”

LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia

“…41 ) It will also be interesting to compare the regulation of LRRTM1 longitudinally during the development of humans and other species, as the imprinted regulation may be restricted to certain developmental periods. 38 In addition, human genetic variation at this locus in nonclinical populations could be analyzed with dense marker genotyping, to test for evidence of selection, particularly with regard to the risk haplotype.…”

Heritability of regional and global brain structure at the onset of puberty: A magnetic resonance imaging study in 9‐year‐old twin pairs

“…A possible explanation for hemispheric asymmetry in genetically influenced brain areas could be that certain genes are predominantly expressed in one hemisphere. For example, it was reported that the LM04 gene (essential for cortical development in mice) was more highly expressed in the right hemisphere than in the left [Sun et al, 2005].…”