Selective gene expression in regions of primate neocortex: Implications for cortical specialization
Highlights
► Genes selectively expressed in primate neocortical areas are reviewed. ► The first group of the genes is selectively expressed in the primary visual area. ► The second group of the genes is selectively expressed in association areas. ► The third group of the genes is selectively expressed in motor areas. ► Implication of such gene expression patterns specific to primates is discussed.
Introduction
The neocortex is a structure that is present only in mammals and is enlarged in primates, particularly in humans (Rakic, 1995, Kaas, 2005). Studies on the brain and mind may have their origin already in ancient Egyptian medicine. However, it took many centuries until the cerebral cortex came into focus and the localization of cortical functions was established (Gross, 1998). Studies on the histological difference in the neocortex including those of Elliott Smith, Campbell, Brodmann and Vogts in the early part of the last century revealed the regional (areal) difference within the cerebral cortex (Haymaker, 1951, Gross, 1998; Rosa and Tweedale, 1998). Neocortical areas are best known by Brodmann's nomenclature in which he defined 52 areas (48 areas in humans) on the basis of his studies on more than 50 mammalian species (Brodmann, 1909, Brodmann, 1914). The delineation of areas is not uniform. Vogt may have recognized more areas than Brodmann (over 200 cortical areas), and Cambell took a more conservative view because he felt the changes between areas were in fact gradual, with a few exceptions (Haymaker, 1951, Rosa and Tweedale, 2005). Even though the precise definition of areas may still change as physiological and histological studies progress (e.g., Felleman and Van Essen, 1991, Kaas, 2005, Rosa and Tweedale, 2005), the importance of cortical parcellation or areas as functional units has been established (Gross, 1998).
There are a number of questions regarding neocortical areas that need to be answered. One important issue is the relationship between the cytoarchitectonic and functional areas. Although the neocortical areas are defined by the difference in their cytoarchitectonic structure within different brain regions, the transition is usually gradual and it is not easy to find defined borders except for core areas such as area 17 (V1) in primates. The boundary of cytoarchitectonic areas is less clear in the areas that appear in progressively later stages of development, or that has appeared in more recent evolution (Rosa and Tweedale, 2005, Collins et al., 2010).
In the 1990s, genes specifically expressed in subsets of neocortical areas were searched for in rodents. In earlier studies using differential display methods, none of the 148 differentially expressed gene fragments that show preference for either the rostral or caudal neocortex of embryonic day 16 (E16) in rats (Liu et al., 2000). From this analysis, it was concluded that neocortical-area-selective genes either did not exist or were very rare. This result suggested that a neocortical area was not defined by the expression of a specific set of genes absolutely restricted to that area, and that each neocortical area was likely defined by the expression of a unique combination of genes, most of which are also expressed in other areas (O’Leary and Nakagawa, 2002). Recent analyses of gene expression patterns and functional significance in rodents reveal that there are four patterning centers that control graded transcription in the neocortex. These centers are as follows. The anterior neural ridge (ANR), which later becomes the commissural plate, produces Fgf (fibroblast growth factor) 8 and Fgf 17, and the cortical hem produces Wnts (winglesss types) and BMPs (bone morphogenetic proteins). The third putative patterning center, the antihem located in the lateral cortex, was identified on the basis of its expression of Tgfα (transforming growth factor alpha), Fgf 7, Sfrp 2 (secreted frizzled receptor 2), Neuregulin 1 and 3. The fourth telencephalic patterning center is located in the ventral telencephalon defined by the expression of sonic hedgehog (Shh), although it does not have defined roles in dorsal telencephalic patterning (O’Leary and Sahara, 2008). However, the mechanisms that control delineation of areas following such gradient wise expressions are not well known (O’Leary and Sahara, 2008).
I hypothesized that it is possible that primates with their much more a realization show certain corresponding molecular specialization beyond that found in rodents. It would be informative to identify the genes that show certain neocortical-area-selective expression patterns in the adult neocortex, because we can trace back the expression patterns of the genes that show marked areal difference at the adult-stage, which may be different at other developmental stages.
It has been studied that the gene expression undergoes dynamic changes through the course of primate neocortical development. For example, neocortical areas mature according to a temporal sequence, which is revealed by markers such as nonphosphorylated neurofilament (NNF) and SlIT1, starting from primary sensory areas such as V1 and S1 (area 3b) and gradually spreading toward association areas (Burman et al., 2007, Sasaki et al., 2010, Hill et al., 2010). The neocortex therefore is formed as a result of dynamic and complex interactions of gene expressions that are non identical at any given stage of its development.
Our approach has been therefore to isolate genes that are specifically expressed in the neocortical areas in primates. In the initial screening, we used the differential display method to isolate the genes specifically expressed in five representative areas; namely, two frontal areas (FDΔ and FA), the temporal association cortex (TE), the early visual association cortex (OA), and the primary visual cortex (OC) (from the nomenclature of Von Bonin and Bailey, 1947). We found three genes that are highly preferentially expressed in specific areas. One such gene is occipital1 (OCC1), which is preferentially expressed in the primary visual cortex in macaques (Tochitani et al., 2001). The second gene is retinol binding protein (RBP), which is preferentially expressed in association areas (Komatsu et al., 2005). The third gene is GDF-7, which is abundant in motor areas (Watakabe et al., 2001). We then systematically screened genes that are specifically expressed in primate neocortical areas. For this screening, we compared tissues derived from four different areas (frontal, temporal, motor, and visual areas), by the restriction landmark cDNA scanning (RLCS) method. The area definition used for RLCS analysis is different from that used for the differential display method because RLCS analysis requires the isolation of a relatively larger amount of RNA than the differential display method. Therefore, we needed to isolate relatively larger areas in RLCS analysis than in the differential display method. In this series of experiments, we screened more than 10,000 spots, which roughly correspond to a similar number of genes whose expression levels are significant in the brain. We found five genes that were expressed at significantly higher levels in specific sets of cortical areas (more than 5-fold difference between areas with the highest and lowest expression levels). Genes that show a marked difference among representative areas can be grouped into two types: the OCC1 and RBP types. The expression pattern reveals large domain structures in the primate neocortex, which may have specifically evolved in primates.
In this review, I will first describe the genes we have isolated and characterized as those that show marked differences in area selectivity in expression pattern in the adult neocortex of macaque monkeys. Then, I will discuss their possible functional significance in the primate neocortex. Finally, I will discuss the implication of these expression patterns in neocortical specialization in primates.
Section snippets
Genes showing neocortical-area-selective expressions
We have identified three groups of genes showing marked neocortical-area-selective expression patterns in primates (Yamamori and Rockland, 2006). The first group includes the primary-sensory-area-selective genes, which are particularly prominent in the primary visual cortex (OCC1, testican-1, testican-2, 5-HT1B, and 5-HT2A). The second group includes association-area-selective genes (RBP, SPARC, PNMA5, and SLITs). The expression patterns of the genes within the first group are similar to each
Functional roles of genes showing neocortical-area-selective expressions
In Section 2, I describe the genes specifically expressed in certain areas of the primate neocortex. These genes can be grouped into two categories: one includes genes preferentially expressed in thalamocortical projection – receiving layers in the visual cortex and the other includes those preferentially expressed in the prefrontal and sensory association areas. Although the complementary expression pattern between these two groups of genes suggests that their functions generally correlate
Area specialization of neocortex
As Brodmann already pointed out, there are considerable variations of the organization of areas among the more than 50 species of mammals he examined. He defined 52 areas in all the species he examined and considered that these cytoarchitectonic structures are basically common in the neocortex cross-species. The variation of the mammalian neocortex may be explained by the combination of the basic structures. For example, he defined up to 48 areas in the human neocortex (Brodmann, 1914).
There
Future directions
To conclude my review, I will discuss possible future research directions with regard to the genes expressed in the primate neocortical areas.
Acknowledgements
This research is supported by a Grant-in-Aid for Scientific Research on Priority Areas (Molecular Brain Science) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. A part of this study is the result of the project, “Highly Creative Animal Model Development for Brain Sciences” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan. I thank Drs. Kathleen Rockland and Sigrun
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