Effects of reduced connexin43 function on skull development in the Cx43I130T/+ mutant mouse that models oculodentodigital dysplasia

Jarvis, Sommer E.; Lee, Jae Eun; Jewlal, Elizabeth; Barr, Kevin; Kelly, Gregory M.; Laird, Dale W.; Willmore, Katherine E.

doi:10.1016/j.bone.2020.115365

Cited by 6 publications

(20 citation statements)

References 40 publications

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“…Cx43 hemichannels are also thought to be important in bone homeostasis 17 . Indeed, Cx43 function has been shown to play a role in osteoblast differentiation, 18‐23 osteocyte mechanosensation in relation to bone remodelling, 22,24‐28 and osteoclast formation and activation 29,30 . While the strong contribution of Cx43 to bone development and homeostasis has been established, here we distinguish its role in skull development as important, but not crucial, in comparative reference to genes critical for skull development such as Wnts and Fgfs .…”

Section: Introductionmentioning

confidence: 84%

“…Heterozygous G60S and I130T mutant mice (hereafter referred to as G60S/+ and I130T/+) exhibit the broad spectrum of craniofacial phenotypes characteristic of patients with ODDD. However, the phenotype is far more severe in G60S/+ mutants compared to I130T/+ mice 23,36,37 . While retaining its capacity to traffic to the cell's surface, the G60S mutant is a loss of function mutant that acts as dominant negative on co‐expressed wildtype Cx43, as seen in reference cells and in mutant mice 36,38‐40 .…”

Section: Introductionmentioning

confidence: 99%

“…The phenotypic difference between mutant models appears to follow a Cx43 dosage effect, as G60S/+ mice exhibit an ~80% reduction in Cx43 gap junction channel function whereas channel function is reduced by ~50%in I130T/+ mutants 21,36,44 . Both models also exhibit delayed osteoblast differentiation, a cell process that is known to be affected by reduced Cx43 function 18‐23 . Thus, both mutations appear to affect similar processes in skull development through compromised Cx43 gap junctional function.…”

Section: Introductionmentioning

confidence: 99%

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Connexin 43 contributes to phenotypic robustness of the mouse skull

Jewlal

Barr

Laird

et al. 2021

Developmental Dynamics

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Background We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively. Results Both mutant strains showed significant differences in skull shape compared to wildtype littermates and while these differences were more severe in the G60S/+ mouse, shape differences were localized to similar regions of the skull in both mutants. However, increased skull shape variation was observed in G60S/+ mutants only. Additionally, covariation of skull structures was disrupted in the G60S/+ mutants only, indicating that while a 50% reduction in Cx43 function is sufficient to cause a shift in mean skull shape, the threshold for Cx43 function for disrupting craniofacial phenotypic robustness is lower. Conclusions Collectively, our results indicate Cx43 can contribute to phenotypic robustness of the skull through a nonlinear relationship between Cx43 gap junctional function and phenotypic outcomes.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Connexin 43 contributes to phenotypic robustness of the mouse skull

Jewlal

Barr

Laird

et al. 2021

Developmental Dynamics

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“…To allow skull size and shape comparisons that can statistically detect differences in variance, a sample of at least 30 heads were obtained from offspring from each group. Mouse heads were fixed in 4% paraformaldehyde for 12 to 24 h (Schmidt et al, 2010) and then embedded in 50‐ml Falcon tubes with 1% agarose to eliminate movement during imaging (Jarvis et al, 2020). Scanning was performed using a GE Locus RS‐9 X‐ray μCT (GE Healthcare) at a resolution of 20 μm isotropic voxel size.…”

Section: Methodsmentioning

confidence: 99%

“…For skull 3D landmark collection, surface reconstructions from each skull µ CT were imported into Checkpoint software (Stratovan Corporation). A total of 57 landmarks were collected from each skull reconstruction and were selected based on skull coverage, repeatability, and previous work from our group (Abitbol et al, 2019; Jarvis et al, 2020). All landmarks were collected twice by the same observer (D.D.)…”

Section: Methodsmentioning

confidence: 99%

Effects of advanced maternal age and acute prenatal alcohol exposure on mouse offspring growth and craniofacial phenotype

Draghici

Barr

Hardy

et al. 2021

Alcoholism Clin & Exp Res

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Background: Prenatal alcohol exposure (PAE) can result in developmental defects that include growth restriction, craniofacial anomalies, and cognitive behavioral deficits, though the presence and severity of these adverse outcomes can vary dramatically among exposed individuals. Preclinical animal models have demonstrated that the dose and timing of PAE account for much, but not all, of this phenotypic variation, suggesting that additional factors mitigate the effects of PAE. Here, we used a mouse model to investigate whether maternal age modulates the effects of PAE on the severity and variation in offspring growth and craniofacial outcomes.Methods: Nulliparous C57BL/6N dams received either an intraperitoneal injection of ethanol (EtOH) or vehicle solution on gestational day 7.5. Dams were divided into four groups: (1) EtOH-treated young dams (6 to 10 weeks); (2) control young dams; (3) EtOH-treated old dams (6 to 7 months); and (4) old control dams. Neonate offspring growth restriction was measured through body mass and organ-to-body mass ratios, while skeletal craniofacial features were imaged using micro-CT and analyzed for size, shape, and variation.Results: PAE and advanced maternal age each increased the risk of low birthweight and growth restriction in offspring, but these factors in combination changed the nature of the growth restriction. Similarly, both PAE and advanced maternal age individually caused changes to craniofacial morphology such as smaller skull size, dysmorphic skull shape, and greater skull shape variation and asymmetry. Interestingly, while the combination of PAE and advanced maternal age did not affect mean skull shape or size, it significantly increased the variation and asymmetry of those measures. Conclusion:Our results indicate that maternal age modulates the effects of PAE, but that the effects of this combination on offspring outcomes are more complex than simply scaling the effects of either factor.

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Discordant growth of nasal cartilage and bone contributes to phenotypic variability of the skull in a mouse model

Book

Moore

Tourigny

et al. 2023

Developmental Dynamics

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Background: We previously determined a nonlinear relationship between connexin 43 (Cx43) function and craniofacial phenotypic variation in the mutant mouse model G60S/+, and that this variation was driven by nasal bone deviation. While nonlinearities in the genotype-phenotype map appear to be common, few studies have looked at the developmental processes that underlie this nonlinearity. Here, we investigated the potential tissue-level developmental determinants of the variation in nasal bone phenotype in G60S/+ mice through postnatal development.Results: The deviated nasal bone phenotype arises by postnatal day 21 and becomes more severe by 3 months in G60S/+ mice. Measures of nasal bone remodeling including the number of osteoclasts, mineralizing surface, mineral apposition rate, and bone formation rate are significantly greater in G60S/+ mice compared to wild-type mice at 2 months, but these differences do not correspond with nasal bone deviation. The degree of nasal bone deviation does significantly and negatively correlate with the ratio between nasal bone and cartilaginous nasal septum length. Conclusions: Our findings indicate that the mean phenotypic changes observed between G60S/+ and wild-type mice are due to reduced bone growth, but the increased phenotypic variation found within mutant mice is due to discordant growth between nasal cartilage and bone. K E Y W O R D S bone remodeling, connexin 43, osteoblasts, osteoclasts, postnatal growth 1 | INTRODUCTION To understand the mechanistic basis of both typical and aberrant morphogenesis, we require a well-developed genotype-to-phenotype map. For structures that are Shae A. Book and Alyssa C. Moore are co-first authors.

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Effects of reduced connexin43 function on skull development in the Cx43I130T/+ mutant mouse that models oculodentodigital dysplasia

Cited by 6 publications

References 40 publications

Connexin 43 contributes to phenotypic robustness of the mouse skull

Connexin 43 contributes to phenotypic robustness of the mouse skull

Effects of advanced maternal age and acute prenatal alcohol exposure on mouse offspring growth and craniofacial phenotype

Discordant growth of nasal cartilage and bone contributes to phenotypic variability of the skull in a mouse model

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