Genetic analysis of posterior medial barrel subfield (PMBSF) size in somatosensory cortex (SI) in recombinant inbred strains of mice
ABSTRACT Quantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits. QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume. Previously, QTL mapping was utilized to examine variation of barrel field size in the somatosensory cortex in a limited number of recombinant inbred (RI) strains of mice. In order to further elucidate the underlying natural variation in mouse primary somatosensory cortex, we measured the size of the posterior medial barrel subfield (PMBSF), associated with the representation of the large mystacial vibrissae, in an expanded sample set that included 42 BXD RI strains, two parental strains (C57BL/6J and DBA/2J), and one F1 strain (B6D2F1). Cytochrome oxidase labeling was used to visualize barrels within the PMBSF.
We observed a 33% difference between the largest and smallest BXD RI strains with continuous variation in-between. Using QTL linkage analysis from WebQTL, we generated linkage maps of raw total PMBSF and brain weight adjusted total PMBSF areas. After removing the effects of brain weight, we detected a suggestive QTL (likelihood ratio statistic [LRS]: 14.20) on the proximal arm of chromosome 4. Candidate genes under the suggestive QTL peak for PMBSF area were selected based on the number of single nucleotide polymorphisms (SNPs) present and the biological relevance of each gene. Among the candidate genes are Car8 and Rab2. More importantly, mRNA expression profiles obtained using GeneNetwork indicated a strong correlation between total PMBSF area and two genes (Adcy1 and Gap43) known to be important in mouse cortex development. GAP43 has been shown to be critical during neurodevelopment of the somatosensory cortex, while knockout Adcy1 mice have disrupted barrel field patterns.
We detected a novel suggestive QTL on chromosome 4 that is linked to PMBSF size. The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.
Full-textDOI: · Available from: Robert Scott Waters, Jun 26, 2015
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ABSTRACT: We describe mechanisms regulating development and plasticity of area patterning of the neocortex, the predominant region of the mammalian cerebral cortex. This process, termed arealization, is regulated by genetic mechanisms intrinsic to the cortex and extra-genetic influences, principally thalamocortical axons (TCAs) relaying input from the sensory periphery to the cortex. Intrinsic genetic mechanisms are based on morphogens secreted by patterning centers positioned at the perimeter of the dorsal telencephalon that generate across the nascent cortex, the graded expression of transcription factors (TFs) in cortical progenitors. TFs with prominent roles in arealization are Emx2, Pax6, Sp8, and COUP-TF1, which determine area patterning by specifying or repressing area identities within cortical progenitors. Emx2 preferentially imparts identities associated with posterior visual areas, Pax6 and Sp8 impart identities associated with anterior frontal/motor areas, and COUP-TF1 represses the function of any TF, including Pax6 and Sp8, that specifies frontal/motor identity. Extra-genetic mechanisms operate within this genetic framework and complement the TFs to help generate area patterning. We review features that characterize areas, contributions of genetic specification to critical features including output projection neurons, consider variants and plasticity of area patterning, and discuss models and concepts of area patterning. We also compare mechanisms of regionalization of the cerebral cortex to neocortical arealization.Patterning and Cell Type Specification in the Developing Cns and Pns, Volume 1 edited by John Rubenstein, Pasko Rakic, 05/2013: chapter Chapter 4 - Area Patterning of the Mammalian Cortex: pages 61-85; Academic Press., ISBN: 978-0-12-397265-1
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ABSTRACT: PURPOSE OF REVIEW: Advances in magnetic resonance microscopy (MRM) make it practical to map gene variants responsible for structural variation in brains of many species, including mice and humans. We review results of a systematic genetic analysis of MRM data using as a case study a family of well characterized lines of mice. RECENT ADVANCES: MRM has matured to the point that we can generate high contrast, high-resolution images even for species as small as a mouse, with a brain merely 1/3000th the size of humans. We generated 21.5-micron data sets for a diverse panel of BXD mouse strains to gauge the extent of genetic variation, and as a prelude to comprehensive genetic and genomic analyses. Here we review MRM capabilities and image segmentation methods; heritability of brain variation; covariation of the sizes of brain regions; and correlations between MRM and classical histological data sets. SUMMARY: The combination of high throughput MRM and genomics will improve our understanding of the genetic basis of structure-function correlations. Sophisticated mouse models will be critical in converting correlations into mechanisms and in determining genetic and epigenetic causes of differences in disease susceptibility.Current opinion in neurology 07/2009; 22(4):379-86. DOI:10.1097/WCO.0b013e32832d9b86 · 5.73 Impact Factor
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ABSTRACT: Arealization of the neocortex is controlled by a regulatory hierarchy beginning with morphogens secreted from patterning centers positioned at the perimeter of the dorsal telencephalon. These morphogens act in part to establish within cortical progenitors the differential expression of transcription factors that specify their area identity, which is inherited by their neuronal progeny, providing the genetic framework for area patterning. The two patterning centers most directly implicated in arealization are the commissural plate, which expresses fibroblast growth factors, and the cortical hem, which expresses bone morphogenetic proteins and vertebrate orthologs of Drosophila wingless, the Wnts. A third, albeit putative, patterning center is the antihem, identified by its expression of multiple signaling molecules. We describe recent findings on roles for these patterning centers in arealization. We also present the most recent evidence on functions of the four transcription factors, Emx2, COUP-TFI, Pax6, and Sp8, thus far implicated in arealization. We also describe screens for candidate target genes of these transcription factors, or other genes potentially involved in arealization. We conclude with an assessment of a forward genetics approach for identifying genes involved in determining area size based in part on quantitative trait locus mapping, and the implications for significant differences between individuals in area size on behavioral performance.Current Opinion in Neurobiology 02/2008; 18(1):90-100. DOI:10.1016/j.conb.2008.05.011 · 6.77 Impact Factor