Cadherin superfamily genes play a role in a wide variety of developmental processes and mature functions of the vertebrate brain. In the present study, we mapped in situ the expression pattern of five classic cadherins (Cdh4, Cdh6, Cdh7, Cdh8, Cdh11) and eight δ-protocadherins (Pcdh1, Pcdh7, Pcdh8, Pcdh9, Pcdh10, Pcdh11, Pcdh17 and Pcdh19) in the primary somatosensory cortex of the adult mouse. All of these cadherins show layer-specific expression profiles in primary somatosensory cortex. Some cadherins (for example, Cdh4, Cdh7, Pcdh8) mark subsets of cells within a given lamina, while other cadherins (Cdh11 and Pcdh10) are expressed more widely in multiple layers. Results from tyramide-based double-fluorescence in situ hybridization (FISH) provide evidence that most single neurons express more than one cadherin in a combinatorial fashion in all layers of cerebral cortex. This combinatorial code is rather comprehensive because pairwise expression of cadherins can assume any type of combination (complementarity, partial or complete overlap, subset-specific expression, cell-size specific expression, etc.). We propose that the combinatorial expression of multiple cadherin genes contributes to the molecular specification of the vast complexity of neurons in cerebral cortex.
"The pattern of expression in the developing human cortex was similar to that reported in the ferret (Krishna-K et al. 2009) and the rat (Kim et al. 2007), and our findings of expression in the adult hippocampal formation and amygdala are similar to observations made in the rat (Kim et al. 2010) and mouse (Hertel et al. 2008). Reports of Pcdh11 expression in the cortex of adult experimental animals are less consistent: Ranging from complete absence in rat (Kim et al. 2007), a subpopulation of neurons in layers IV–VI in the mouse somatosensory cortex (Krishna-K et al. 2011), to layers II–VI of the mouse motor cortex (Hertel and Redies 2011), and layers II–VI of the ferret visual cortex (Krishna-K et al. 2009). Interneuron expression was not specifically addressed by these studies; however, work on γ-Pcdhs demonstrates widespread interneuronal expression in many structures (Wang et al. 2002; Phillips et al. 2003; Lefebvre et al. 2008). "
[Show abstract][Hide abstract] ABSTRACT: Protocadherins 11X and 11Y are cell adhesion molecules of the δ1-protocadherin family. Pcdh11X is present throughout the mammalian radiation; however, 6 million years ago (MYA), a reduplicative translocation of the Xq21.3 block onto what is now human Yp11 created the Homo sapiens-specific PCDH11Y. Therefore, modern human females express PCDH11X whereas males express both PCDH11X and PCDH11Y. PCDH11X/Y has been subject to accelerated evolution resulting in human-specific changes to both proteins, most notably 2 cysteine substitutions in the PCDH11X ectodomain that may alter binding characteristics. The PCDH11X/Y gene pair is postulated to be critical to aspects of human brain evolution related to the neural correlates of language. Therefore, we raised antibodies to investigate the temporal and spatial expression of PCDH11X/Y in cortical and sub-cortical areas of the human fetal brain between 12 and 34 postconceptional weeks. We then used the antibodies to determine if this expression was consistent in a series of adult brains. PCDH11X/Y immunoreactivity was detectable at all developmental stages. Strong expression was detected in the fetal neocortex, ganglionic eminences, cerebellum, and inferior olive. In the adult brain, the cerebral cortex, hippocampal formation, and cerebellum were strongly immunoreactive, with expression also detectable in the brainstem.
"Tdrd3 (tudor domain containing 3) codes for a novel stress granule-associated protein, which interacts with FMRP, the protein of the gene associated with Fragile X syndrome, thereby implicating it as a potential contributor to this disorder (Linder et al., 2008). Pcdh9 belongs to the δ1 non-clustering protocadherin family (Kim et al., 2011), and is part of a network of cadherins and protocadherins that have been linked to laminar specification in the neocortex (Hertel and Redies, 2011; Krishna et al., 2011). Pcdh9 is one of a network of genes that has recently been linked to schizophrenia and bipolar disorder though its association with GSK3β/β-catenin signaling (Pedrosa et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The corpus callosum is the main commissure connecting left and right cerebral hemispheres, and varies widely in size. Differences in the midsagittal area of the corpus callosum (MSACC) have been associated with a number of cognitive and behavioral phenotypes, including obsessive-compulsive disorders, psychopathy, suicidal tendencies, bipolar disorder, schizophrenia, autism, and attention deficit hyperactivity disorder. Although there is evidence to suggest that MSACC is heritable in normal human populations, there is surprisingly little evidence concerning the genetic modulation of this variation. Mice provide a potentially ideal tool to dissect the genetic modulation of MSACC. Here, we use a large genetic reference panel - the BXD recombinant inbred line - to dissect the natural variation of the MSACC. We estimated the MSACC in over 300 individuals from nearly 80 strains. We found a 4-fold difference in MSACC between individual mice, and a 2.5-fold difference among strains. MSACC is a highly heritable trait (h(2) = 0.60), and we mapped a suggestive QTL to the distal portion of Chr 14. Using sequence data and neocortical expression databases, we were able to identify eight positional and plausible biological candidate genes within this interval. Finally, we found that MSACC correlated with behavioral traits associated with anxiety and attention.
Frontiers in Genetics 05/2012; 3:91. DOI:10.3389/fgene.2012.00091
"Recently, several excellent articles have been published comparing some of the type II cadherin expression to that of some protocadherins in the mammalian cerebellum (Neudert et al., 2008), visual (Krishna et al., 2009), and somatosensory cortex (Krishna et al., 2011) and they provide an excellent coverage of Cdh6, Cdh7, Cdh8, and Cdh11 expression in the examined areas both in developing and adult brains. Not surprisingly, layerspecific expression of these genes was scrambled in the reeler mutant known for its severely delaminated cortical structure (Hertel and Redies, 2011). "
[Show abstract][Hide abstract] ABSTRACT: The type II classic cadherin subfamily contains a number of extensively studied genes (cdh6, cdh8, cdh11); however, the expression and function of the other members have only been partially described. Here we employed reverse-transcription polymerase chain reaction (RT-PCR) and in situ hybridization to characterize cortical and hippocampal expression of all type II cadherins (with the exception of the nonneural Cdh5) in the developing and adult mouse brain. Many of these genes have ubiquitous mRNA distribution patterns throughout development, indicating high functional redundancy, which might be necessary for safe production of the strictly laminated structure of these regions. A few of the genes examined, however, exhibit a unique spatiotemporal pattern of expression, particularly during cortical development, indicating a potentially specific function. In the developing and adult hippocampus, almost all of these genes are strongly expressed in glutamatergic neurons of the CA1-CA3 pyramidal cell layer and the granular layer of the dentate gyrus. In contrast, there are significant expression differences within the GABAergic cells of the adult hippocampus. Our results indicate that selective expression of type II cadherins may generate a flexible cell-adhesion machinery for developing neurons to selectively bind to each other, but can also provide a high level of security due to the multiple overlaps in the expression domains.
The Journal of Comparative Neurology 05/2012; 520(7):1387-1405. DOI:10.1002/cne.22801 · 3.23 Impact Factor
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