Genome-wide analyses of human perisylvian cerebral cortical patterning

Abstract

Despite the well established role of the frontal and posterior perisylvian cortices in many facets of human-cognitive specializations, including language, little is known about the developmental patterning of these regions in the human brain. We performed a genome-wide analysis of human cerebral patterning during midgestation, a critical epoch in cortical regionalization. A total of 345 genes were identified as differentially expressed between superior temporal gyrus (STG) and the remaining cerebral cortex. Gene ontology categories representing transcription factors were enriched in STG, whereas cell-adhesion and extracellular matrix molecules were enriched in the other cortical regions. Quantitative RT-PCR or in situ hybridization was performed to validate differential expression in a subset of 32 genes, most of which were confirmed. LIM domain-binding 1 (LDB1), which we show to be enriched in the STG, is a recently identified interactor of LIM domain only 4 (LMO4), a gene known to be involved in the asymmetric pattering of the perisylvian region in the developing human brain. Protocadherin 17 (PCDH17), a neuronal cell adhesion molecule, was highly enriched in focal regions of the human prefrontal cortex. Contactin associated protein-like 2 (CNTNAP2), in which mutations are known to cause autism, epilepsy, and language delay, showed a remarkable pattern of anterior-enriched cortical expression in human that was not observed in mouse or rat. These data highlight the importance of expression analysis of human brain and the utility of cross-species comparisons of gene expression. Genes identified here provide a foundation for understanding molecular aspects of human-cognitive specializations and the disorders that disrupt them.cortex ͉ microarray ͉ gene expression ͉ evolution ͉ CASPR2

Shining a light on CNTNAP2: complex functions to complex disorders

“…In the human cortex, CNTNAP2 is expressed in layers II-V 10 with enrichment in Broca's area and other perisylvian brain regions. 40 The enriched expression of CNTNAP2 in these brain regions, known to be important for speech and language, is consistent with the emerging role for CNTNAP2 in normal language development in humans.…”

“…During human brain development, its expression is highest in frontal and anterior lobes, striatum and dorsal thalamus. 18,40 This expression pattern recapitulates the cortico-striato-thalamic circuitry known to modulate higher order cognitive functions, including speech and language, reward, and frontal executive function. In the human cortex, CNTNAP2 is expressed in layers II-V 10 with enrichment in Broca's area and other perisylvian brain regions.…”

“…40,41 At later developmental stages and in postnatal mice, Cntnap2 is diffusely expressed in the cortex, striatum, thalamus, hypothalamus, periaqueductal grey and superior colliculus. 10,40,41 Additionally, Cntnap2 is strongly expressed in the hippocampal formation in development and in adulthood. 10,41 Recently, Cntnap2 expression has been comprehensively analysed in the Zebra finch brain.…”

Advances in autism genetics: on the threshold of a new neurobiology

“…Other recent work demonstrates that both rare single-base-pair mutations 38 and common variation in CNTNAP2 (Refs 39 ,40 ) could also contribute to ASD risk. Although CNTNAP2 is best known for clustering potassium channels along myelinated axons, data from the human fetal brain indicate expression at high levels before myelination 41 . Along with evidence for abnormalities in neuronal migration in Amish patients who are homozygous for the frameshift mutation, these data suggest additional unappreciated functionality and an important role for this gene in the development of brain regions that are likely to be important for autism.…”

“…Such efforts are likely to provide important insights not only into ASD but also into related disorders in which behaviour is compromised through impaired function of overlapping regions and circuits. Because genes modulate behaviour through complex temporal and positional expression, analyses of candidate genes both through development 41 and in patient material (for example, the Autism Tissue Program) will be important. Advances in systems biology should provide an important platform on which to integrate the modulatory effects of multiple interacting genes with functional data compiled from many levels of analysis 83,84 .…”