Cartilage-Specific and Cre-Dependent Nkx3.2 Overexpression In Vivo Causes Skeletal Dwarfism by Delaying Cartilage Hypertrophy

Jeong, Da Un; Choi, Je Yong; Kim, Dae Won

doi:10.1002/jcp.25446

Cited by 11 publications

(9 citation statements)

References 64 publications

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“…Limb defects have not been reported in mouse mutants (Herbrand et al, 2002;Lettice et al, 1999;Tribioli and Lufkin, 1999), but changes in the regulation of Nkx3.2 expression have been linked to tibia length (Castro et al, 2019), suggesting that the gene has a similar role in humans and mice and that the reason limb defects have not been found in mouse mutants is that the mutation is perinatally fatal, while these limb phenotypes appear postnatally (Hellemans et al, 2009). These results are consistent with a common role for Nkx3.2 in repressing chondrocyte maturation and therefore endochondral bone formation, as downregulation or gene knockout results in longer endochondral limb and median fin bones in all three species (Castro et al, 2019;Hellemans et al, 2009), and Nkx3.2 overexpression in mice causes the opposite -skeletal dwarfism (Jeong et al, 2017).…”

Section: Discussionsupporting

confidence: 64%

The Broad Role of Nkx3.2 in the Development of the Zebrafish Axial Skeleton

Waldmann

Leyhr

Zhang

et al. 2020

Preprint

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The transcription factor Nkx3.2 (Bapx1) is an important chondrocyte maturation inhibitor. Previous Nkx3.2 knock-down and overexpression studies in non-mammalian gnathostomes have focused on its role in primary jaw joint development, while little is known about the function of this gene in broader skeletal development. We generated CRISPR/Cas9 knockout of nkx3.2 in zebrafish and applied a range of techniques to characterize skeletal phenotypes at developmental stages from larva to adult, revealing fusions in bones of the occiput, the loss or deformation of bony elements derived from basiventral cartilages of the vertebrae, and an increased length of the proximal radials of the dorsal and anal fins. These phenotypes are reminiscent of Nkx3.2 knockout phenotypes in mammals, suggesting that the function of this gene in axial skeletal development is ancestral to osteichthyans. Our results highlight the broad role of nkx3.2 in zebrafish skeletal development and its context-specific functions in different skeletal elements.

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Section: Discussionsupporting

confidence: 64%

The Broad Role of Nkx3.2 in the Development of the Zebrafish Axial Skeleton

Waldmann

Leyhr

Zhang

et al. 2020

Preprint

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“…One of the gene regions under selection was associated with Homeobox gene NKX3-2, which is involved in skeletal development, specifically in the ossification and longitudinal growth of bone (Jeong et al 2017). Selection for genes involved in skeletal development between krill-feeding and fish feeding seal colonies could be a result of the very high levels of fluoride which are found in krill, but not in fish.…”

Section: Biological Function Of Genomic Regions Under Selectionmentioning

confidence: 99%

Prey differences drive local genetic adaptation in Antarctic fur seals

Cleary¹,

Bester²,

Forcada³

et al. 2019

Mar. Ecol. Prog. Ser.

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Antarctic fur seal, Arctocephalus gazella, colonies are found on sub-Antarctic islands around the continent. These islands experience a range of conditions in terms of physical and biological habitat, creating a natural laboratory to investigate local genetic adaptation. One striking habitat difference is in the availability of Euphausia superba krill as prey, which has led to A. gazella exhibiting a range of diets. A. gazella in some colonies consuming exclusively krill, while their conspecifics in other colonies feed mainly on fish and consume few to no krill. To investigate potential adaptations to these different prey fields, reduced representation genome sequencing was conducted on A. gazella from all eight of the major colonies. Twenty seven genomic regions exhibiting signatures of natural selection were identified. Two of these genomic regions were clearly associated with seals living in krilldominated areas or those in fish-dominated areas. Twenty-two additional genomic regions under selection showed a pattern consistent with prey differences as the driver of selection, after historical migrations from krill-dominated habitats where lineages evolved to present krill-poor habitat areas were taken into account. Only one of the genomic regions identified appeared to be explained by any other environmental variable analysed (depth). Genomic regions under prey-driven selection included genes associated with regulation of gene expression, skeletal development, and lipid metabolism. Adaptation to local prey has implications for spatial management of this species, and for the potential impacts of climate or harvest driven reductions in krill abundance on these seals.

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“…As described above, many papers, including our own work (12,13,15,17), have shown that NKX3.2 expression is associated with reduced chondrocyte hypertrophy, and thus maintenance of a healthy AC phenotype. Taking the mechanism into consideration described by Im and Kim, this would imply that under healthy cartilage conditions where NKX3.2 expression is relatively high, HIF1α would be more effectively targeted for degradation.…”

mentioning

confidence: 80%