Spontaneous malformations of the cerebellar vermis: Prevalence, inheritance, and relationship to lobule/fissure organization in the C57BL/6 lineage

Dine, Sarah E. Van; Siu, Nga Yan; Toia, Alyssa R.; Cuoco, Joshua A.; Betz, Adrienne J.; Bolivar, Valerie J.; Torres, Germán; Ramos, Raddy L.

doi:10.1016/j.neuroscience.2015.09.025

Cited by 10 publications

(17 citation statements)

References 42 publications

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“…2(g–i), MLH observed in Cre- driver lines in this database had cytoarchitecture and histological profiles identical to heterotopia observed in C57BL/6 mice (Fig. 2d–f) [19, 20]. As indicated in Table 1, we found that all but 3 of 91 Cre- driver lines exhibiting MLH were maintained on a congenic C57BL6/J background.…”

Section: Resultssupporting

confidence: 73%

“…Methods for harvesting brains, tissue sectioning, staining, and identification of heterotopia have been extensively described by our group [19, 20, 22]. In the present report, all brains examined were from mice older than postnatal day (P) 14.…”

Section: Methodsmentioning

confidence: 99%

“…The mechanisms underlying MLH formation are unknown; however, heterotopia formation is a heritable and weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles [20]. One predication from earlier findings suggests that MLH should be observed in GE mice either (1) produced with C57BL/6 ES cells or (2) backcrossed to a C57BL/6 background.…”

Section: Introductionmentioning

confidence: 99%

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Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background

Cuoco

Esposito²,

Moriarty³

et al. 2017

Cerebellum

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C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the posterior vermis, indicative of neuronal migration defect during cerebellar development. Recognizing that many genetically engineered (GE) mouse lines are produced from C57BL/6 ES cells or backcrossed to this strain, we performed histological analyses and found that cerebellar heterotopia were a common feature present in the majority of GE lines on this background. Furthermore, we identify GE mouse lines that will be valuable in the study of cerebellar malformations including diverse driver, reporter, and optogenetic lines. Finally, we discuss the implications that these data have on the use of C57BL/6 mice and GE mice on this background in studies of cerebellar development or as models of disease.

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Section: Resultssupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background

Cuoco

Esposito²,

Moriarty³

et al. 2017

Cerebellum

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“…Consequently, we used well-established histological methods [25–27] to examine brains from numerous inbred mice including: 129S6/SvEvTac (n=20), 129S1/SvImJ (n=17), A/J (n=17), BALB/cJ (n=16), DBA/2J (n=20), FVB/NJ (n=18) strains. We used methods previously described [25,27,39,41,42] to examine high-resolution digital histological material from the Mouse Strains dataset from the ABA, including 129S1/SvImJ (n=117 cases), C57BL/6J (n=314), Cast/EiJ (n=117 cases), DBA/2J (n=117 cases), PWD/PhJ (n=93 cases), SPRET/EiJ (n=117 cases), WSB/EiJ (n=93 cases) strains. Remarkably, we did not observe MLH in any inbred strain except C57BL/6J brains in the ABA Mouse Strains dataset.…”

Section: Resultsmentioning

confidence: 99%

“…We also used digital histological data from the Allen Brain Atlas (ABA; www.brain-map.org) and Mouse Brain Architecture Project (MBAP; http://mouse.brainarchitecture.org) to document heterotopia as previously described [25,27,39,41,42]. Data from the ABA Mouse Strains dataset contains high-resolution sagittal and coronal sections from the following strains (The Jackson Laboratory): 129S1/SvlmJ, C57BL/6J, Cast/EiJ, DBA/2J, PWD/PhJ, SPRET/EiJ, WSB/EiJ.…”

Section: Methodsmentioning

confidence: 99%

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Toia

Cuoco

Esposito

et al. 2017

Neuroscience Letters

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Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

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Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders

et al. 2017

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Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with newly discovered sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but highly exposed adults reportedly have an increased risk of Parkinson's disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect sensitivity to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr Cyp1a2(-/-) mice were most sensitive compared with poor-affinity Ahr Cyp1a2(-/-) and wild-type Ahr Cyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological, and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated toxicity with reduced thymus and spleen weights and significantly reduced thyroxine at P14 in PCB-exposed pups. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immunostaining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity Ahr Cyp1a2(-/-) while Ahr Cyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson's disease.

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Spontaneous malformations of the cerebellar vermis: Prevalence, inheritance, and relationship to lobule/fissure organization in the C57BL/6 lineage

Cited by 10 publications

References 42 publications

Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background

Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders

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