Leveraging comparative genomics to elucidate the genetic determinants of limb skeletal proportion

利用比较基因组学阐明肢体骨骼比例的遗传决定因素

基本信息

项目摘要

The length of each skeletal element changes independently during development and evolution to transform an embryonic skeleton with similar sized cartilages into a diverse array of adult forms and functions. Loss of function mutations of many genes produce proportionately dwarfed skeletons that suggest a common “toolkit” is required for elongation of all of the long bones. Far less well understood, however, are the mechanisms that establish the specific rate and duration of elongation at each growth plate, which together determine adult limb skeletal proportion. What are the genes that define skeletal proportion? Is differential growth controlled by modular enhancers that locally tune expression of genes common to all growth plates and/or by genes that function only in subsets of growth plates? Our laboratory is positioned to answer these profoundly important questions about how vertebrate limbs acquire form and function using two uniquely suitable species: the laboratory mouse and the lesser Egyptian jerboa. Among the nearest mouse relatives, the jerboa has the most extremely different hindlimbs with extraordinarily long feet, but its forelimbs are similar to the mouse. These similarities and differences coupled with high genome sequence homology enable the identification of genetic mechanisms that locally control skeletal growth rate. RNA-Seq analysis of mouse and jerboa forelimb and hindlimb elements revealed that 10% of orthologous genes are differentially expressed correlating with relative growth rates within and between species. These include 40 genes with strong evidence for enhancer modularity in both species. Aim 1 will implement comparative ATAC-Seq and mouse transgenesis to identify and functionally test modular enhancers in the mouse and jerboa genomes. We predict that some of these 40 genes are controlled by radius/ulna enhancers that are conserved between species and by distinct metatarsal enhancers that functionally diverged in jerboa and allowed the uncoupled evolution of jerboa hindlimb proportion. Our expression data also provides a valuable opportunity to fill critical gaps in our understanding of the genes that regulate limb skeletal growth and proportion in all vertebrates. We previously showed that IGF1 signaling is required in mice for hypertrophic chondrocyte size differences in growth plates that elongate at different rates. Although IGF1 has a well-established role in whole organism and organ growth, it is unclear how the pathway is locally regulated to modulate differential growth. In Aim 2, we will biochemically test the hypothesis that elevated protease expression in rapidly elongating skeletal elements cleaves IGF binding proteins thus freeing bioactive IGF1 protein for signaling to accelerate growth. Although six other high priority candidate genes are also expected to be critical regulators of skeletal growth, they have not yet been attributed growth plate functions. Aim 3 will implement a powerful overexpression approach in chicken embryos to test the hypothesis that each of these genes is sufficient to accelerate or inhibit limb growth rate.
每个骨骼元素的长度在发育和进化过程中独立变化

项目成果

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Kimberly Lynn Cooper其他文献

Kimberly Lynn Cooper的其他文献

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{{ truncateString('Kimberly Lynn Cooper', 18)}}的其他基金

Development of approaches to apply CRISPR/Cas9-mediated gene conversion to model complex genetic traits in mice
开发应用 CRISPR/Cas9 介导的基因转换来模拟小鼠复杂遗传性状的方法
  • 批准号:
    10565297
  • 财政年份:
    2023
  • 资助金额:
    $ 37.86万
  • 项目类别:
Engineering and validation of two conditional multi-gene mouse models of skeletal development
两种条件多基因小鼠骨骼发育模型的工程和验证
  • 批准号:
    10215395
  • 财政年份:
    2020
  • 资助金额:
    $ 37.86万
  • 项目类别:
Engineering and validation of two conditional multi-gene mouse models of skeletal development
两种条件多基因小鼠骨骼发育模型的工程和验证
  • 批准号:
    10043332
  • 财政年份:
    2020
  • 资助金额:
    $ 37.86万
  • 项目类别:
Leveraging comparative genomics to elucidate the genetic determinants of limb skeletal proportion
利用比较基因组学阐明肢体骨骼比例的遗传决定因素
  • 批准号:
    9895624
  • 财政年份:
    2019
  • 资助金额:
    $ 37.86万
  • 项目类别:
Leveraging comparative genomics to elucidate the genetic determinants of limb skeletal proportion
利用比较基因组学阐明肢体骨骼比例的遗传决定因素
  • 批准号:
    10599856
  • 财政年份:
    2019
  • 资助金额:
    $ 37.86万
  • 项目类别:
Leveraging comparative genomics to elucidate the genetic determinants of limb skeletal proportion
利用比较基因组学阐明肢体骨骼比例的遗传决定因素
  • 批准号:
    9762600
  • 财政年份:
    2019
  • 资助金额:
    $ 37.86万
  • 项目类别:
An exploration of the mechanisms of naturally occurring limb muscle loss during neonatal development
新生儿发育过程中自然发生的肢体肌肉丧失机制的探索
  • 批准号:
    9882964
  • 财政年份:
    2019
  • 资助金额:
    $ 37.86万
  • 项目类别:
Leveraging comparative genomics to elucidate the genetic determinants of limb skeletal proportion
利用比较基因组学阐明肢体骨骼比例的遗传决定因素
  • 批准号:
    10382419
  • 财政年份:
    2019
  • 资助金额:
    $ 37.86万
  • 项目类别:
MicroRNA Function in the Developing Vertebrate Limb
MicroRNA 在脊椎动物肢体发育中的功能
  • 批准号:
    7237363
  • 财政年份:
    2006
  • 资助金额:
    $ 37.86万
  • 项目类别:
MicroRNA Function in the Developing Vertebrate Limb
MicroRNA 在脊椎动物肢体发育中的功能
  • 批准号:
    7425332
  • 财政年份:
    2006
  • 资助金额:
    $ 37.86万
  • 项目类别:

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