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

• 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
• 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

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 这是对“视黄酸的局部调节 颅骨形成中的信号传导”。颅骨位置是胚胎外胚层的局部增厚 在开发过程中区分以指定脊椎动物头中的关键结构，包括配对的感觉 器官和感觉颅神经节。所有颅骨位置均来自一个称为 平台前区域（PPR）。响应于周围组织的提示，PPR最终分离 沿着胚胎的前轴轴形成不同的位置结构域，该结构域包含特定细胞类型 到每个感觉的位置：腺型植物学，嗅觉，镜头，三叉神经，epibranchial和Eot 安置。破坏位置规范的突变导致广泛的先天性先天缺陷 以失明或死亡形式的感觉丧失或垂体引起的马酮失衡为特征 缺陷以及对口面区域的感觉能量的丧失。因为颅骨的机制 规格知之甚少，干预和临床改善结果的策略有限 这些缺陷。 Saint-Jeannet实验室使用Xenopus laevis研究颅面的基本机制 其蓝图的发展高度构成了所有脊椎动物。实验室的先前研究具有 证明锌指转录因子ZIC1促进了非单细胞自主的命运 通过激活视黄酸（RA）信号通路的方式。最新基因中有RA 分解代谢酶CYP26C1和RA调节的同源域转录因子PITX2C。初步的 结果表明，CYP26C1对于PPR规范很重要，并且在防止过量RA方面发挥作用 积累。此外，发现PITX2C和CYP26C1共享一个共同的表达领域 占据ZIC1诱导RA合成和前瞻性PPR的前神经板之间的区域。 基于这些观察，我假设CYP26C1参与RA的局部退化 为了建立RA水平的适当阈值，随后可以激活PITX2C介导 PPR形成的基因表达。我将结合发育，遗传和高 吞吐量筛选方法以确定CYP26C1和PITX2C如何调节RA水平的RA水平 PPR的适当空间定位，还鉴定出在PPR形成中起关键作用的新型基因。这 研究将解决我们所知的当前差距，即如何将形态学梯度在局部调制到 调节特定细胞的基因表达，还将发现与颅骨有关的新基因 Placode规范。这项研究的发现将提供对位置机制的更深入的见解 规格并将阐明影响感官器官的颅面缺陷的分子基础。