Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice

Salehi, Pezhman; Myint, Anthony; Kim, Young J; Ge, Marshall; Lavinsky, Joel; Ho, Maria K.; Crow, Amanda L.; Cruz, C.; Monges-Hernadez, Maya; Wang, Juemei; Hartiala, Jaana; Zhang, Li I.; Allayee, Hooman; Lusis, Aldons J.; Ohyama, Takahiro; Friedman, Rick A.

doi:10.1007/s10162-016-0578-4

Cited by 2 publications

(4 citation statements)

References 53 publications

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“…The significance level for the GWAS threshold using the HMDP was determined by the familywise error rate (FWER), which is the probability of detecting one or more false positives across all SNPs/phenotype. These parameters were similar to previous studies utilizing the HMDP …”

Section: Methodssupporting

confidence: 90%

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Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis

Hiyari

Green

Pan

et al. 2018

Journal of Bone and Mineral Research

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Periodontitis (PD) is characterized by bacterial infection and inflammation of tooth-supporting structures and can lead to tooth loss. PD affects ∼47% of the US population over age 30 years and has a heritability of about 50%. Although the host immunoinflammatory response and genetic background play a role, little is known of the underlying genetic factors. We examined natural genetic variation in lipopolysaccharide (LPS)-induced PD across a panel of inbred mouse strains, the hybrid mouse diversity panel (HMDP). We observed a strain-dependent sixfold difference in LPS-induced bone loss across the HMDP with a heritability of 53%. We performed a genomewide association study (GWAS) using FAST-LMM, which corrects for population structure, and identified loci significantly associated with PD. We examined candidate genes at a locus on chromosome 5, which suggested a relationship between LPS-induced bone loss and, together with expression data, identified Cxcl family members as associated with PD. We observed an increase in Cxcl10 protein, as well as immune cells and pro-inflammatory cytokines in C57BL/6J (high bone loss strain) but not in A/J (low bone loss strain) after LPS injections. Genetic deletion of CXCR3 (Cxcl9 and10 receptor) demonstrated a ∼50% reduction in bone loss and reduced osteoclasts after LPS injections. Furthermore, WT mice treated with AMG-487 (a CXCR3 antagonist) showed a ∼45% reduction in bone loss and decreased osteoclasts after LPS injections. We conclude that CXCR3 is a strong candidate for modulating the host response in individuals susceptible to PD. © 2018 American Society for Bone and Mineral Research.

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Section: Methodssupporting

confidence: 90%

“…Statistical analysis for the GWAS on LPS‐induced periodontal bone loss was performed following previous GWAS studies utilizing the HMDP . Genotypes of ∼500,000 SNPs were obtained from the mouse diversity array.…”

Section: Methodsmentioning

confidence: 99%

Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis

Hiyari

Green

Pan

et al. 2018

Journal of Bone and Mineral Research

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“…The Netrin receptor, Deleted in Colorectal Carcinoma (DCC), expressed in SAG neurons, seems to guide axons to their targets in the cochlea and vestibular patches. In mouse embryos mutant for DCC, axons are misrouted and show disrupted bifurcation patterns 37,38 . However, the expression of Netrin in the cochlea is weak, and KO mice show normal auditory innervation.…”

Section: Innervation Of the Auditory And Vestibular Systemmentioning

confidence: 99%

“…In mouse embryos mutant for DCC, axons are misrouted and show disrupted bifurcation patterns. 37 , 38 However, the expression of Netrin in the cochlea is weak, and KO mice show normal auditory innervation. Therefore, it remains to be determined whether other secreted molecules could serve as DCC ligands in the cochlea.…”

Section: Innervation Of the Auditory And Vestibular Systemmentioning

confidence: 99%

Wiring the senses: Factors that regulate peripheral axon pathfinding in sensory systems

Nomdedeu‐Sancho

Alsina

2022

Developmental Dynamics

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Sensory neurons of the head are the ones that transmit the information about the external world to our brain for its processing. Axons from cranial sensory neurons sense different chemoattractant and chemorepulsive molecules during the journey and in the target tissue to establish the precise innervation with brain neurons and/or receptor cells. Here, we aim to unify and summarize the available information regarding molecular mechanisms guiding the different afferent sensory axons of the head. By putting the information together, we find the use of similar guidance cues in different sensory systems but in distinct combinations. In vertebrates, the number of genes in each family of guidance cues has suffered a great expansion in the genome, providing redundancy, and robustness. We also discuss recently published data involving the role of glia and mechanical forces in shaping the axon paths. Finally, we highlight the remaining questions to be addressed in the field.

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Genome-Wide Association Analysis Identifies Dcc as an Essential Factor in the Innervation of the Peripheral Vestibular System in Inbred Mice

Cited by 2 publications

References 53 publications

Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis

Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis

Wiring the senses: Factors that regulate peripheral axon pathfinding in sensory systems

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