Foxp2 and Foxp1 are recently identified members of the Fox family of winged-helix/forkhead transcription factor genes. A recent study has found that mutations in human FOXP2 produce a severe language disorder. Since Foxp2 appears to be important in language, we wanted to explore the expression of this gene and a homologous gene, Foxp1, in the developing brain. In the present study, we investigated the time course and localization of Foxp2 and Foxp1 mRNA and protein expression in the developing and adult mouse using in situ hybridization and immunohistochemistry. Foxp2 and Foxp1 are expressed as early as E12.5 and persist into adulthood. Foxp2 and Foxp1 were most highly expressed in the developing and mature basal ganglia. Expression of Foxp2 was also observed in the cerebral cortex (layer 6), cerebellum (Purkinje neurons), and thalamus. Foxp1 expression was observed in the cerebral cortex (layers 3-5), hippocampus (CA1), and thalamus. Very little ventricular zone expression was observed for Foxp2 and Foxp1 and the expression of both of these genes occurred following neuronal migration, suggesting a role for these genes in postmigratory neuronal differentiation. Furthermore, we demonstrated the expression of FOXP2 in human fetal brain by RT-PCR, in the perisylvian area of the left and right cerebral hemispheres, as well as in the frontal and occipital cortices. Overall, the widespread expression of Foxp2 in the developing brain makes it difficult to draw specific conclusions about which areas of Foxp2 expression are critical to human language function.

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...