Gene Regulatory Networks that Establish Mandible and Maxilla Patterning

建立下颌骨和上颌骨模式的基因调控网络

基本信息

  • 批准号:
    10454286
  • 负责人:
  • 金额:
    $ 59.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Abstract Craniofacial abnormalities affecting the mandible, maxilla and jaw joint are commonly encountered birth defects, most of which require surgical correction to establish quality of life and in some cases survival. While one or more organizing centers within the developing pharyngeal arches, from which the face arises, may hold the key to understanding the etiologies of these defects, the existence of such centers has never been proven, leading to a poor understanding of how gene regulatory networks are regulated and integrated during facial development. This limiting knowledge stifles new approaches to efficaciously treat these deformities. Endothelin1 (through DLX proteins) and BMP (through SMAD proteins) signaling establishes positional and structural identity of neural crest cells within the ventral mandibular arch. This is primarily achieved by induction of the basic bHLH transcription factor HAND2. HAND2 and BMP synergy is required for induction of the bHLH factor HAND1 within the ventral-most “cap” of the mandibular arch. Interestingly, altering HAND1 dimer partner choice (thus altering HAND1-mediated signaling) results in pronounced mid-facial clefting, even though Hand1 is not expressed in the mid-face structures. Our data shows that loss of either BMP or HAND2 activity disrupts the establishment of the ventral cap. These findings establish our hypothesis that the intersection of BMP and HAND2 activity establishes a ventral cap-signaling center, which acts in both cell and non-cell autonomous manners to drive upper and lower jaw development. Additionally, we hypothesize that DLX activity antagonizes BMP/HAND2 synergy. This proposal takes advantage of the craniofacial development expertise of Dr. David Clouthier, the bHLH signaling expertise of Dr. Anthony Firulli and a number of novel mutant mouse alleles to test these hypotheses in two Aims. In Aim 1, we will use single cell (sc) RNA-seq to define the gene regulatory networks that are initiated by the coordinated action of both HAND2 and BMP that act either in an autonomous (ventral cap) or non-cell autonomously (more dorsal first arch areas) manner. Following analysis of scRNA-seq data, the top HAND2/BMP effector candidates will be functionally evaluated in loss-of-function and genetic studies. In Aim 2, the role of DLX proteins in confining ventral cap size will be examined using a novel gain-of- function Dlx5 mouse allelefollowed by functional testing of DLX action by creating a Hand1 mouse mutant lacking DLX cis-element inputs. Together, these novel approaches will provide the first direct evidence that the mandibular arch ventral cap is a signaling center required for facial development. Relevance: Craniofacial abnormalities are common and require intensive reconstructive surgical corrections. HAND2 and BMPs play key roles in patterning the neural crest cells that form the face. Gaining insight into the molecular mechanism of this understudied developmental process could have great potential for initial development of non-surgical treatments for congenital craniofacial defects in patients.
摘要

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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David E. Clouthier其他文献

Hand2 loss leads to aglossia from failure to repress Dlx5/6
  • DOI:
    10.1016/j.ydbio.2009.05.519
  • 发表时间:
    2009-07-15
  • 期刊:
  • 影响因子:
  • 作者:
    David E. Clouthier;Marthe Howard;Francie Hyndman
  • 通讯作者:
    Francie Hyndman
Transcriptional regulation of hand2 in zebrafish neural crest cells and cardiomyocytes
  • DOI:
    10.1016/j.ydbio.2010.05.192
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jennifer Ikle;David E. Clouthier
  • 通讯作者:
    David E. Clouthier
prdm genes in zebrafish craniofacial development
  • DOI:
    10.1016/j.ydbio.2010.05.190
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Letitia Kwok;David E. Clouthier;Kristin B. Artinger
  • 通讯作者:
    Kristin B. Artinger
<strong>Aglossia in Hand2 conditional knockout mutants results from misregulation of Dlx5/6</strong>
  • DOI:
    10.1016/j.ydbio.2010.05.129
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Francie E. Hyndman;Marthe Howard;David E. Clouthier
  • 通讯作者:
    David E. Clouthier

David E. Clouthier的其他文献

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{{ truncateString('David E. Clouthier', 18)}}的其他基金

Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
  • 批准号:
    10057669
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
  • 批准号:
    10210382
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
  • 批准号:
    10653143
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
  • 批准号:
    10175020
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
  • 批准号:
    10611514
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
  • 批准号:
    10402929
  • 财政年份:
    2020
  • 资助金额:
    $ 59.85万
  • 项目类别:
Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
  • 批准号:
    8750599
  • 财政年份:
    2014
  • 资助金额:
    $ 59.85万
  • 项目类别:
Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
  • 批准号:
    9237250
  • 财政年份:
    2014
  • 资助金额:
    $ 59.85万
  • 项目类别:
Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
  • 批准号:
    8865602
  • 财政年份:
    2014
  • 资助金额:
    $ 59.85万
  • 项目类别:
Hand2 Function and Regulation During Craniofacial Development
Hand2 颅面发育过程中的功能和调节
  • 批准号:
    8401463
  • 财政年份:
    2009
  • 资助金额:
    $ 59.85万
  • 项目类别:

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