Local modulation of retinoic acid signaling in cranial placode formation

颅板形成中视黄酸信号的局部调节

基本信息

批准号：
9913995
负责人：
Aditi Dubey
金额：
$ 7.01万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913995
关键词：
Address Adopted Affect Anosmia Anterior Anterior Pituitary Gland Biological Models Blindness Caregivers Cells Cephalic Cleft lip with or without cleft palate Clinical Complex Congenital Abnormality Coupled Craniofacial Abnormalities Cues Data Defect Development Developmental Biology Dose Early Intervention Ectoderm Embryo Embryonic Development Enzymes Etiology Future Ganglia Gene Expression Genes Head Healthcare Hormone imbalance Knowledge Labyrinth Light Liquid Chromatography Location Measures Mediating Metabolism Molecular Mutation Nature Olfactory Epithelium Optics Organ Otic Placodes Patients Pharmacology Pituitary Gland Play Positioning Attribute Process Production Quality of life Regulation Role Saints Sensory Signal Induction Signal Pathway Signal Transduction Structure Testing Therapeutic Intervention Tissues To specify Transcript Tretinoin Trigeminal System Vertebrates Work Xenopus Xenopus laevis Zinc Fingers base cell type craniofacial development craniofacial disorder deafness developmental genetics experimental study high throughput screening homeodomain improved improved outcome inhibitor/antagonist insight lens loss of function morphogens neural plate novel orofacial prevent progenitor programs prospective response socioeconomics tandem mass spectrometry transcription factor transcriptome sequencing

项目摘要

ABSTRACT This is a revised submission of application #1F32DE027599-01 on the “local modulation of retinoic acid signaling in cranial placode formation”. Cranial placodes are focal thickenings of the embryonic ectoderm that differentiate during development to specify key structures in the vertebrate head, including paired sensory organs and sensory cranial ganglia. All cranial placodes arise from a common progenitor territory called the pre-placodal region (PPR). In response to cues from the surrounding tissues, the PPR eventually segregates along the anterior-posterior axis of the embryo to form distinct placodal domains that contain cell-types specific to each of the sensory placodes: the adenohypophyseal, olfactory, lens, trigeminal, epibranchial and otic placodes. Mutations that disrupt placode specification cause a wide range of congenital birth defects that are characterize by sensory loss in the form of blindess or deafness, or hormone imbalances due to pituitary defects, and loss of sensory enervation to the orofacial region. Because the mechanisms of cranial placode specification are poorly understood, there are limited strategies to intervene and clinically improve the outcome of these defects. The Saint-Jeannet Lab uses Xenopus laevis to study the basic mechanisms of craniofacial development as their blueprint highly conserved across all vertebrates. Previous studies in the lab have demonstrated that the zinc-finger transcription factor Zic1 promotes placodal fate in a non-cell autonomous manner by activating retinoic acid (RA) signaling pathway. Among the genes upregulated are the RA catabolizing enzyme Cyp26c1 and an RA-regulated homeodomain transcription factor Pitx2c. Preliminary results suggest that Cyp26c1 is important for PPR specification and plays a role in preventing excess RA accumulation. Additionally, Pitx2c and Cyp26c1 were found to share a common domain of expression that occupies the region between anterior neural plate, where Zic1 induces RA synthesis, and the prospective PPR. Based on these observations, I hypothesize that Cyp26c1 participates in local degradation of RA in order to establish the appropriate threshold of RA levels, which can subsequently activated Pitx2c-mediated gene expression for the formation of PPR. I will use a combination of developmental, genetic and high throughput screening approaches to determine how Cyp26c1 and Pitx2c modulate RA levels for the appropriate spatial positioning of PPR, and also identify novel genes that play key roles in PPR formation. This study will address current gaps in our knowledge as to how morphogen gradients are locally modulated to regulate gene expression in particular cells, and will also uncover new genes that are involved in cranial placode specification. The findings from this study will provide deeper insights into the mechanisms of placode specification and will shed light on the molecular basis for craniofacial defects affecting sensory organs.

抽象的这是申请 #1F32DE027599-01 的修订提交，内容涉及“视黄酸的局部调节” 颅板是胚胎外胚层的局部增厚部分，在发育过程中进行区分，以指定脊椎动物头部的关键结构，包括配对的感觉器官和感觉颅神经节所有颅板都起源于称为“脑”的共同祖区。前基板区 (PPR) 响应周围组织的信号，最终分离。沿着胚胎的前后轴形成包含特定细胞类型的独特基板区域每个感觉基板：腺垂体、嗅觉、晶状体、三叉神经、上鳃和耳破坏基板规范的突变会导致多种先天性出生缺陷。其特征是感觉丧失，表现为失明或耳聋，或由于垂体导致的激素失衡由于颅板的机制，口面部区域的缺陷和感觉减弱。对规范知之甚少，干预和临床改善结果的策略有限 Saint-Jeannet 实验室利用非洲爪蟾来研究颅面畸形的基本机制。发育作为其蓝图在所有脊椎动物中都高度保守。证明锌指转录因子 Zic1 在非细胞自主性中促进基板命运上调的基因包括 RA。分解代谢酶 Cyp26c1 和 RA 调节的同源域转录因子 Pitx2c。结果表明 Cyp26c1 对于 PPR 规范很重要，并在防止过量 RA 中发挥作用此外，Pitx2c 和 Cyp26c1 被发现共享一个共同的表达域。占据前神经板（Zic1 诱导 RA 合成）和预期 PPR 之间的区域。基于这些观察，我认为 Cyp26c1 按顺序参与 RA 的局部降解建立适当的 RA 水平阈值，随后激活 Pitx2c 介导的基因表达对于PPR的形成我将结合发育、遗传和高水平。通量筛选方法以确定 Cyp26c1 和 Pitx2c 如何调节 RA 水平 PPR 的适当空间定位，并鉴定在 PPR 形成中起关键作用的新基因。研究将解决目前我们在如何局部调节形态发生素梯度方面的知识空白调节特定细胞中的基因表达，还将发现与颅脑相关的新基因这项研究的结果将为基板的机制提供更深入的见解。规范并将揭示影响感觉器官的颅面缺陷的分子基础。