Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

Figure 30.4 The anatomical locations of the medial RALDH3 band are indicated for P15 in the form of a color code (visible in color plate 20), in which prefrontal includes the prelimbic and medial orbital cortices; cingulate includes areas 1 and 2 of the cingulate cortex; motor designates mostly the secondary motor cortex, in addition to a small caudal part of the primary motor cortex; parietal includes the medial and lateral parietal association cortices; and medial extrastriate extends from a location where the rostral extrastriate region abuts the parietal association cortex all the way caudally, an elongated region also called area 18b or V2M (Wagner et al., 2006). See color plate 20.

RALDH3 colocalizes with markers for neuronal plasticity

When the shifted stable RALDH3 band is compared with a range of cytoarchitectonic characteristics at different postnatal ages, some of the markers show strikingly differential

The RALDH3 band represents a tangential pattern that emerges very late, only after the first postnatal week in mice. Because the tangential organization of the cortex is determined irreversibly already during embryonic development but the results of the early determination events become visible only postnatally (Grove and Fukuchi-Shimogori, 2003), we wondered which factors act upstream of RALDH3 and bring about its postnatal pattern (Wagner et al., 2006). One of these appears to be neurotrophin-3 (NT-3), whose normal expression is compared to RALDH3 in figure 30.6. Strong NT-3 along the medial embryonic cortex precedes RALDH3; during P1–P2 the territories of the two markers overlap briefly, but over the next few days they change into tangentially complementary domains. Along the rostromedial limbic cortex, where RALDH3 remains strong, NT-3 expression fades, and caudomedially, where RALDH3 shifts from medial limbic regions into adjoining neocortex, strong

Figure 30.5 A–D, Stacks of coronal cortex sections illustrating the delay in maturation of parvalbumin and neurofilaments along the RALDH3 band, as well as the persistence of the immature form

of the neural cell adhesion molecule PSA-NCAM (Wagner et al., 2006).

NT-3 expression persists in all retrosplenial areas. Like RALDH3, the NT-3 pattern seems to remain constant throughout life, but its levels diminish. Because of this intriguing relationship between the two markers, we tested RALDH3 expression in conditional NT-3 knockout mice (Wagner et al., 2006): in the absence of NT-3, RALDH3 is present but fails to undergo its normal lateral shift, instead maintaining its normally transient early postnatal expression pattern. The cytoarchitectonic markers with differential expression along the RALDH3 band in normal cortex shift to match the abnormal RALDH3 in the NT-3 null mutants (not shown here).

RALDH3 and NT-3 define distinct maturation patterns in the postnatal cortex

Figure 30.7 (left) summarizes the topographical changes in RALDH3 expression and its relationship to NT-3, as projected onto the postnatal cortex surface. At P2 the two markers transiently occupy the same territory along the medial edge of the cortex, but subsequently their expressions change gradually into two topographically complementary patterns. In coronal brain sections the stable, shifted patterns can be adequately diagnosed from three samples: sections at the level of the cingulate cortex, the parietal association

Figure 30.7 Left, Schematic surface view of the transient cortical territories occupied by RALDH3 and NT-3 early postnatally and of the shifted stable expression patterns. Right, Neighboring coronal sections through a P8 normal mouse brain labeled for RALDH3, NT-3, and perineuronal nets, illustrated for three anteroposterior

cortex, and the medial peristriate cortex, which contains the dorsal visual stream (figure 30.7, right). A comparison of the patterns with several cytoarchitectonic characteristics shows that both RALDH3 and NT-3 colocalize with developmental expression differentials, which are often opposite in direction. This point is illustrated for the maturation of perineuronal nets detected with Wisteria lectin; the appearance of these extracellular structures is known to gradually limit the plasticity of cortical neurons by cementing synapses in place and restricting the perineuronal diffusion space (Koppe et al., 1997). At the sites of RALDH3 expression, which are indicated by the black arrows in figure 30.7, maturation of perineuronal nets is suppressed, and at the NT-3 sites (white arrows), their maturation is relatively advanced.

These colocalizations do not allow the conclusion that either RALDH3 or NT-3 induces these patterns; rather, the two factors delineate in the postnatal cortex distinct topographical territories with separate maturation properties that may be opposite in direction. Since the patterns are reflected in several very ordinary and commonly studied cytoarchitectonic characteristics, we expected that they would have been identified and named in classic neuroanatomy. However, while all the details that we observe are in agreement with known features of particular cortical regions, the entire RALDH3-colocalized band has not been recognized previously or given a comprehensive name, and we adhere here to our preliminary nomenclature.

BGEM data bank searches

To explore at what time in development a shifted pattern can first be detected for any gene, we turned to the Brain

levels at the cingulate, parietal cortex, and dorsal visual stream, as indicated by the horizontal arrows. Sections at the corresponding levels are also shown for perineuronal nets at P11 and P21. Note that perineuronal-net maturation is delayed at RALDH3 (black arrows) and accelerated at NT-3 (white arrows).

Gene Expression Map (BGEM) database (www.stjudebgem. org/web/mainPage/mainPage.php). This site contains in situ hybridization images for four ages: E10, E17, P7, and P42. We searched through all the 2,200 genes that were included soon after the Web site was published (Magdaleno et al., 2006). Although this search was necessarily cursory, no shifted patterns were detectable for any gene among the embryonic data. Among the P7 data, most of the genes with differential expression in the medial cortex still resemble the early transient patterns shown for P2 in figure 30.7, but for several genes, some shifted characteristics are apparent. Among the P42 data, however, multiple genes display strikingly shifted, RALDH3-colocalized expression patterns. From the BGEM searches we concluded that the patterns we observe are clearly the main patterns for all genes with differential expression along the medial cortex, and that a shifted, RALDH3-colocalized pattern emerges only relatively late during postnatal cortex maturation.

Allen Brain Atlas searches

Because the BGEM data bank is limited with respect to adult ages, we searched the Web site of the Allen Brain Atlas (www.brainatlas.org/aba/), which lists expression data for 21,000 mouse genes (Lein et al., 2007). This Web site contains an enormous amount of data collected by nonradioactive in situ hybridizations of fully adult (P56) brains and photographed at low and higher magnifications. Because we are trying to characterize patterning across the entire postnatal cortex, we chose low-resolution dark-field pictures, which are sufficient for detection of transcortical patterns. For figure 30.8 the same three levels as in figure 30.7

were selected out of the serial sections available in the Allen database, while the full evaluation was based on inspection of all sections. The Allen data show that the transient midline patterns present at P2 have practically disappeared by P56 and are replaced by the two stable patterns represented by RALDH3 and NT-3. Within both territories a gene can be differentially upor downregulated, and if differential expression is visible for both regions, it is most often in the opposite direction. A few genes, however, are regulated in the same directions in the two territories.

So far, we have found 370 genes whose mRNA levels are upregulated (304 genes) or downregulated (66 genes) along the entire RALDH3 band. Figure 30.8 shows a few examples of genes from the Allen Brain Atlas Web site that are differentially upor downregulated along RALDH3, in

addition to three genes whose expression is upregulated within the NT-3 territory. For multiple technical reasons, the search results up to now represent only a fraction of all the genes that must be differentially regulated along the cortical midline, and chance was involved in the detection of patterned expression. First, the patterns can only be satisfactorily distinguished in coronal sections, but the Allen team screened all genes initially in parasagittal sections; only when potentially interesting patterns became detectable were the genes also processed for visualization in the coronal plane. Second, for many genes, expression is difficult to evaluate even in coronal sections owing to underexposure of the preparations with respect to the cortex. Third, all the Allen data are on P56, whereas we found that some differences are more pronounced earlier during cortex maturation.

Figure 30.8 Coronal sections through an adult mouse brain labeled for RALDH3 and NT-3 by immunohistochemistry are compared with dark-field views from the Allen Web site of representative coronal sections, labeled by in situ hybridizations for dif-

ferent genes. The medial RALDH3 and NT-3 expression patterns are enhanced to accentuate the topographical parallels between these low-magnification images.

Evaluations of the data bank searches

To detect a trend in the assortment of identified genes, we performed ontology searches with the Pathway Express program for the RALDH3 colocalized genes (Draghici et al., 2003). The most common pathways are neuroactive ligandreceptor interactions and the MAPK and CamK signaling pathways. This result differs from corresponding ontology searches performed by Balmer and Blomhoff (2002) for all the genes they found to be regulated by RA in the most recent literature survey: they obtained a flat ontology distribution, indicative of RA roles in many different cellular functions throughout the body. If one assumes that RA causes the differential expression of the genes along the RALDH3 band, the differences between the ontology searches point to unique properties of RA signaling in the brain. Our assumption that RA itself represents a significant factor is supported by the similarity in regulation that apparently occurs in response to RA diffusing from either RALDH3 or RALDH2, as is obvious in the thumbnail views in figure 30.8 and in other images from the data banks: in most cases, the expression of the genes that are upregulated along the RALDH3 band is also strong in upper cortical regions close to the RALDH2 expression in the meninges. Among the patterns of downregulated genes, both the RALDH3 band and the uppermost cortical layers appear relatively empty.

The ontology search results relate to the notion, explained earlier, that we think the unusually strong RA signaling in the brain is due to a convergence with CREB-activated gene expression and a mutual amplification. Canon et al. (2004) describe that RA can rapidly activate CREB via ERK (MAPK) phosphorylation in a nongenomic pathway; interestingly, they report that RA-mediated CREB activation lasts much longer than neurotrophin-mediated activation. In preliminary comparisons of the group of shifted genes with CREB-regulated genes (Lonze and Ginty, 2002; Cawley et al., 2004; Carlezon et al., 2005), we find a significant overlap. As the activation of CREB-dependent gene expression requires Ser-133 phosphorylation of CREB, we performed preliminary Western blots with a pCREB antibody, which showed that pCREB levels are elevated along both the RALDH3 and the NT-3 bands compared with other cortical regions (Luo et al., 2008).

One of the known factors contributing to CREB’s enormous range of highly specific gene expression is that it causes transcription of other transcription factors, with which it collaborates in combinatorial transcriptional codes (Lonze and Ginty, 2002; Cawley et al., 2004). Among the best characterized examples are the immediate early genes, including c-fos, whose mRNA levels rise within minutes of CREB activation but always return to baseline within a brief time even if CREB phosphorylation persists. Canon et al. (2004) report that c-fos is also rapidly upregulated following

RA applications to neuronal cultures and that this occurs via nongenomic mechanisms, because the c-fos promoter does not contain an RA response element. c-Fos is known to form heterodimers with members of the jun family of transcription factors and to bind to AP1 sites contained in the promoters of many genes. Searches through the Allen database show that both c-fos and junB are upregulated along the RALDH3 band (not shown here). This chronic elevation of immediate early genes, which cannot be explained by CREB activation alone, is one of the arguments in support of the notion that RA and CREB act in concert along the shifted location.

A related intriguing property of the preliminary shifted gene list is that it contains a high fraction of factors directly or indirectly involved in transcription, which has also been recognized as a common characteristic of genes implicated in cognitive diseases (Hong et al., 2005). Examples are several other transcription factors, as well as coregulators with enzymatic activities implicated in epigenetic mechanisms, including acetylation, methylation, phosphorylation, ADP-ribosylation, ubiquitination, and ATP-dependent chromatin remodeling. A differential expression of components in the transcriptional apparatus is bound to influence gene transcription, a process known to be exquisitely sensitive to protein levels and gene dosage, as is apparent in the rapid proteasome-mediated turnover of all transcriptional components and in the severe consequences of CBP coactivator reduction in Rubinstein-Taybi syndrome (Hong et al., 2005; Rochette-Egly, 2005; Lonard and O’Malley, 2006; Rosenfeld et al., 2006). The RALDH3 colocalized genes contain many that are compromised in different cognitive diseases, including genes implicated in mental retardation syndromes, Alzheimer’s disease, candidate genes for autism, schizophrenia, and other psychiatric disorders. An interesting example is the Chd7 gene, a chromodomain helicase recently identified as being mutated in CHARGE syndrome (Vissers et al., 2004), a form of mental retardation in which one-third of the cases also show autism. The CHARGE syndrome consists of a nonrandom association of ocular coloboma (C), heart anomaly (H), choanal atresia (A), retarded growth or development (R), genital hypoplasia (G), and ear anomalies or hearing impairment (E). This combination of malformations is practically identical to retinoid embryopathy (Wilson et al., 1953; Shenefelt, 1972); in fact, choanal atresia is the reason that simple RALDH3 null mutant mice die shortly after birth (Dupe et al., 2003). Localization of the Chd7 gene has been described by in situ hybridization both for human and mouse embryos (Bosman et al., 2005): its levels are highest at sites with RALDH expression or lacZ labeling in the RA-reporter mice. The Allen data show that Chd7 is upregulated in the adult cortex along the RALDH3 band, as is also the case for the Mecp2 gene mutated in Rett syndrome, another form of syndromic autism.

The dorsal visual stream

The visual system of mice is organized according to the same basic plan found in all mammals and best characterized in primates. A main difference between mice and primates is the amount of space the brain devotes to the projections from different parts of the retina. Whereas in primates the central visual representations of the fovea are disproportionately magnified, mice do not have a fovea but a broad horizontal region of the retina that is relatively enlarged in central visual maps. Although this streak-like specialization is not apparent in simple histological preparations of the retina, it is strikingly obvious as differential RA distribution in retinas of RA reporter mice (Dräger et al., 2001; Luo et al., 2006). Like primates, mice have retinal ganglion cells of different sizes and functional properties that convey different aspects of visual information in the parallel magnoand parvocellular pathways to the cortex (Merigan and Maunsell, 1993). In higher peristriate areas the two visual pathways feed into physically divergent systems (Wang and Burkhalter, 2004). The dorsal stream that receives the magnocellular input acts in spatial and motion perception; it contains the information about “where” a stimulus is located. The ventral stream, by contrast, functions as cognitive pathway that carries the information about “what” a stimulus is (Merigan and Maunsell, 1993; Goodale and Westwood, 2004; Wang and Burkhalter, 2004). The dorsal visual stream integrates with other sensory input in parietal regions, and the combined information is propagated rostrally into areas in which attentional and executive processes are generated (Coogan and Burkhalter, 1993; Dolan, 2002; Wang and Burkhalter, 2004).

As described earlier, the caudal part of the RALDH3 band contains the dorsal visual stream (Wang and Burkhalter, 2004), which is likely relevant for its higher neuronal

plasticity and late maturation in humans (Braddick et al., 2003; Goodale and Westwood, 2004). These characteristics were demonstrated in psychophysical studies of specific visual skills in children: dorsal stream function, including perception of motion and vernier acuity, develops later and remains plastic for a much longer time than color and form vision, which are processed in the ventral stream (Skoczenski and Norcia, 2002; Mitchell and Neville, 2004). Moreover, dorsal stream function is known to be selectively affected in several human cognitive syndromes (Braddick et al., 2003). Visual impairments restricted to the dorsal stream in the presence of normal ventral stream function accompany Williams syndrome (Braddick et al., 2003; Meyer-Lindenberg et al., 2006), dyslexia (Buchholz and McKone, 2004), autism (Pellicano et al., 2005), and schizophrenia (Schechter et al., 2003; Keri et al., 2004), and they are also a prominent defect in low-birth-weight children (Downie et al., 2003). Premature birth is a classic condition of vitamin A deficiency, because the retinol storage capacity of the human liver develops late: it is always insufficient in premature babies and slowly reaches its capacity only later in childhood (Shenai, 1999).

The etiology of some of the syndromes with dorsal stream abnormalities involves both genetic and environmental contributions, including schizophrenia (Schechter et al., 2003; Keri et al., 2004) and autism (Pellicano et al., 2005); others are mainly due to mutations, including Williams syndrome, which is caused by a hemizygous microdeletion of about 28 genes (Meyer-Lindenberg et al., 2006). Because the size and location of the deletion can vary between individuals affected with Williams syndrome, the critical genes for the cognitive symptoms have been identified; using fMRI, Meyer-Linden- berg et al. (2006) mapped the locations of functional abnormalities to the dorsal visual stream of the human brain (figure 30.9, left). Comparisons of the human data with the

Figure 30.9 Left, Illustration from a review by Meyer-Lindenberg et al., (2006) on Williams syndrome. Interrupted arrow indicates the localization of functional abnormalities. Right, Allen data bank

expressions of the three genes in the mouse cortex that have been linked to the cognitive defects in humans, and comparison with RALDH3.

localizations in the Allen atlas show that the expression of all three cognition-linked genes is differentially regulated along the RALDH3 band (figure 30.9, right): the general transcription factor Gtf2i and the cytoplasmic linker Cyln2 are slightly higher, and the LIM domain containing kinase Limk1 is slightly lower in this territory. Although all three genes are expressed throughout the cortex, as are most of the genes implicated in cognitive functions, we suggest that their differential expression along the RALDH3 band ought to differentially accentuate this anatomical location with respect to functional abnormalities that are caused by the halved gene dosage in Williams syndrome.

Conclusion

From our own histological examinations and the gene expression data searches we conclude that the postnatally emerging RALDH3 band along the medial cortex demarcates a pivotal postnatal patterning event for functional characteristics that has not previously been recognized as a coherent arrangement. The entire complement of genes with differential regulation along the shifted, RALDH3colocalized location can be assumed to contain some that are directly influenced by RA, some that might act upstream of RALDH3 expression, and others that might be mainly responsive to any one of the shifted genes. Available information does not allow placing a gene in any of these three categories, and recent advances in the molecular biology of transcriptional specificity indicate that these categories are not clear-cut alternatives (Rochette-Egly, 2005; Lonard and O’Malley, 2006; Rosenfeld et al., 2006). This point has been most thoroughly investigated for the transcription factor CREB, which represents the site of convergence for about 300 physiological and pathological stimuli (Lonze and Ginty, 2002; Cawley et al., 2004; Johannessen et al., 2004). Each one of these stimuli results in the same CREB phosphorylation at Ser-133, which then initiates nuclear responses that are, however, different and appropriate for every stimulus. This amazing specificity of gene expression is now believed to be largely generated at the level of gene transcription, on which intracellular signaling cascades converge together with other determinants, including the ligand availability for nuclear receptors, to influence dynamically changing coregulator interactions with the basic transcriptional apparatus (Kadonaga, 2004; Rosenfeld et al., 2006). From the observations that RA responses are preferentially amplified in the brain, we suspect that the combinatorial mechanisms for specific gene expression must be unusually complex in the brain.

acknowledgments Experimental work was supported by grants EY01938 and EY13272 from the National Eye Institute. For the gene expression data in the mouse brain,

we are greatly indebted to the team of the Allen Brain Atlas (www.brain-map.org) and the BGEM team (www. stjudebgem.org/web/mainPage/mainPage.php). We thank Yasuo Sakai for the NT-3 reporter brains (figure 30.6) and James Crandall and Peter McCaffery for reading the manuscript.

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