Development Genetics of Tooth Number Variation in Sticklebacks

刺鱼牙齿数量变异的发育遗传学

• 批准号: 10641680
• 负责人: Craig Thomas Miller
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641680
• 关键词: Adult; Affect; Alleles; BMP6 gene; Biological Assay; Biological Models; Biology; Candidate Disease Gene; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dental; Dentistry; Dentition; Development; Developmental Biology; Dyes; Engineering; Enhancers; Epithelium; Fishes; Fresh Water; Gasterosteidae; Gene Expression; Genes; Genetic; Genetic study; Genomic Segment; Genomics; Goals; Hair; Heritability; Human; In Vitro; Individual; Jaw; Knowledge; Label; Learning; Life; Ligands; Maps; Mesenchymal; Mesenchyme; Molecular; Mus; Mutation; Natural regeneration; Oral; Organ; Organogenesis; Outcome; Pathway interactions; Pattern; Persons; Pharyngeal structure; Phenotype; Physiologic pulse; Population; Positioning Attribute; Research; Signal Pathway; Signal Transduction; Skin; System; Testing; Tooth regeneration; Tooth structure; Transgenic Organisms; Variant; Vertebrates; WNT Signaling Pathway; Work; appendage; deciduous tooth; developmental genetics; experimental study; genetic analysis; genome editing; hair regeneration; human old age (65+); in vitro regeneration; in vivo; insight; loss of function; marine; mutant; offspring; organ regeneration; public health relevance; regenerative

Project Summary The long-term goal of this project is to identify the genetic circuitry regulating tooth formation and replacement. As 30 percent of people worldwide over the age of 65 have no natural teeth, understanding how teeth regenerate is a major goal in biology. Furthermore, teeth, like most organs, form through repeated reciprocal signaling between epithelia and mesenchyme. Thus, understanding the genetic basis of tooth formation and replacement is important both for understanding organogenesis in general, as well as for understanding how teeth can be regenerated in vitro and ultimately in vivo. Teeth are homologous to other vertebrate skin appendages including mammalian hair, and shared genes regulate both tooth and hair formation. Although genetic studies in humans, mice and other vertebrates have identified signaling pathways involved in tooth formation, less is known about how genes regulate tooth replacement. In contrast, how genes regulate mammalian hair regeneration is much more understood. One parsimonious hypothesis is that teeth and hair regenerate using similar genetic circuits. Fish retain the ancestral jawed vertebrate condition of constant tooth replacement throughout adult life. Fish also fertilize their offspring externally in large numbers, providing powerful systems for developmental biology and genetic analyses. Threespine stickleback fish (Gasterosteus aculeatus) offer a new and powerful system to learn the genetic basis of tooth formation and replacement. Relative to low-toothed marine ancestors, derived freshwater populations evolve major heritable increases in tooth number and tooth replacement rates. The different forms can be crossed in the lab, enabling detailed and unbiased forward genetic analyses to map factors controlling the changes in tooth number. Genetic and genomic experiments have mapped one genomic region controlling tooth number to a cis-regulatory intronic tooth enhancer of the Bone Morphogenetic Protein 6 (Bmp6) gene in one high-toothed population. Relative to the marine enhancer, the freshwater enhancer displays expanded tooth epithelial expression, and reduced tooth mesenchymal expression, suggesting these spatial shifts in enhancer activity underlie evolved increases in tooth number. Furthermore, in mice, BMP signaling negatively regulates hair regeneration, and in fish BMP signaling negatively regulates tooth replacement. Together these data support the hypothesis of shared genetic circuitry regulating tooth and hair regeneration. To test this hypothesis, three specific aims are proposed. First, transgenic and genome editing experiments will determine which mutations in the freshwater Bmp6 enhancer affect expression differences and tooth number. Second, genome editing experiments will determine Wnt ligand function during tooth formation and replacement. Third, vital dye pulse-chase experiments will test whether tooth replacement is coordinated within a tooth field. Together these aims will reveal fundamental knowledge of the developmental genetic circuitry regulating tooth formation and replacement, and provide further tests of the hypothesis that teeth regenerate similar to mammalian hair.

项目摘要 该项目的长期目标是确定调节牙齿形成和替换的遗传电路。 由于全世界65岁以上的人中有30%没有天然牙齿， 再生是生物学的主要目标。此外，牙齿，像大多数器官一样，通过重复的相互作用形成。 上皮和间充质之间的信号传导。因此，了解牙齿形成的遗传基础， 替代对于理解器官发生以及理解如何 牙齿可以在体外并最终在体内再生。牙齿与其他脊椎动物的皮肤同源 包括哺乳动物毛发在内的附属物，共同的基因调节牙齿和毛发的形成。虽然 对人类、小鼠和其他脊椎动物的遗传研究已经确定了与牙齿相关的信号通路， 然而，对于基因如何调控牙齿替换，我们知之甚少。相反，基因如何调节 哺乳动物的毛发再生被更多地理解。一个简单的假设是牙齿和头发 利用相似的基因回路再生鱼类保留了有颌脊椎动物的祖先牙齿不变的特征 在整个成年生活中的替代品。鱼类也会在外部大量受精， 发育生物学和遗传分析的强大系统。三棘鱼（Gasterosteus aculeatus）提供了一个新的和强大的系统，以了解牙齿形成和更换的遗传基础。 相对于低齿的海洋祖先，衍生的淡水种群进化出主要的遗传增加， 牙齿数量和牙齿更换率。不同的表格可以在实验室中交叉， 无偏正向遗传分析，以绘制控制牙齿数量变化的因素。遗传和 基因组实验已经将一个控制牙齿数量的基因组区域映射到顺式调节内含子， 牙齿增强骨形态发生蛋白6（Bmp6）基因在一个高齿人群。相对于 海洋增强剂，淡水增强剂显示扩大的牙齿上皮表达， 牙齿间充质表达，表明增强子活性的这些空间转移是进化增加的基础。 齿数。此外，在小鼠中，BMP信号负调节毛发再生，在鱼类中， 信号传导负调控牙齿替换。这些数据共同支持共享的假设 调节牙齿和毛发再生的遗传线路。为了检验这一假设，有三个具体目标： 提出了首先，转基因和基因组编辑实验将确定淡水中的哪些突变 Bmp6增强子影响表达差异和牙齿数目。其次，基因组编辑实验将 确定Wnt配体在牙齿形成和替换过程中的功能。第三，活体染料脉冲追踪 实验将测试牙齿替换是否在牙齿区域内协调。这些目标将 揭示了调节牙齿形成的发育遗传电路的基本知识， 替代，并提供进一步的测试的假设，牙齿再生类似哺乳动物的头发。

项目成果

Grand Challenges in Comparative Tooth Biology

比较牙齿生物学的巨大挑战

• DOI: 10.1093/icb/icaa038
• 发表时间: 2020
• 期刊: Integrative and Comparative Biology
• 影响因子: 2.6
• 作者: Hulsey, C Darrin;Cohen, Karly E;Johanson, Zerina;Karagic, Nidal;Meyer, Axel;Miller, Craig T;Sadier, Alexa;Summers, Adam P;Fraser, Gareth J
• 通讯作者: Fraser, Gareth J

Site pleiotropy of a stickleback Bmp6 enhancer.

• DOI: 10.1016/j.ydbio.2022.09.012
• 发表时间: 2022-12
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Rowley, Alyssa J.;Square, Tyler A.;Miller, Craig T.
• 通讯作者: Miller, Craig T.

Distinct tooth regeneration systems deploy a conserved battery of genes.

• DOI: 10.1186/s13227-021-00172-3
• 发表时间: 2021-03-25
• 期刊: EvoDevo
• 影响因子: 4.1
• 作者: Square TA;Sundaram S;Mackey EJ;Miller CT
• 通讯作者: Miller CT

Evolved Bmp6 enhancer alleles drive spatial shifts in gene expression during tooth development in sticklebacks.

• DOI: 10.1093/genetics/iyab151
• 发表时间: 2021-12-10
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Stepaniak MD;Square TA;Miller CT
• 通讯作者: Miller CT

Modular skeletal evolution in sticklebacks is controlled by additive and clustered quantitative trait Loci.

刺鱼的模块化骨骼进化是由加性和集群数量性状基因座控制的。

• DOI: 10.1534/genetics.114.162420
• 发表时间: 2014
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Miller,CraigT;Glazer,AndrewM;Summers,BrianR;Blackman,BenjaminK;Norman,AndrewR;Shapiro,MichaelD;Cole,BonnieL;Peichel,CatherineL;Schluter,Dolph;Kingsley,DavidM
• 通讯作者: Kingsley,DavidM