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Role of the novel regulator lbh in neural crest and craniofacial development

新型调节器 lbh 在神经嵴和颅面发育中的作用

基本信息

批准号：
8901768
负责人：
Kara E Powder
金额：
$ 5.88万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Craniofacial malformations are among the most common human birth defects, affecting 1/700 births. While many of the genes that underlie these defects are known, the identity and functions of many others are not. The overarching goal of this proposal is evaluate the role of a largely uncharacterized gene, limb bud and heart homolog (lbh), during zebrafish craniofacial development. This gene may mediate CHARGE syndrome, a disease of neural crest cells (NCCs) that includes craniofacial defects such as micrognathia. Additionally, we have associated this gene with the evolution of jaws in cichlids, an evolutionary model that exhibits extensive diversity in craniofacial form, many of which mimic human facial malformations. Combined, these data led to the hypothesis that lbh is a novel regulator of NCC and craniofacial development, which will be tested through the following experimental aims. Aim 1: Given the paucity of information about lbh, we will first characterize the expression pattern and cellular specificity of lbh throughout zebrafish facial development using whole-mount and sectioned in situ hybridization and comparison with known craniofacial markers. Aim 2: We will evaluate the effects of modulating lbh expression (morpholino knockdown or mRNA overexpression) on the craniofacial skeleton. Preliminary experiments indicate that depletion of Lbh results in reduction of NCCs and commensurate defects in the craniofacial skeleton. Specifically, we will determine if the cellular mechanism of this defect is due to a failure of induction, failure of migration, decreased survival, or premature differentiatin of NCCs using a combination of in situ hybridization, reporter zebrafish strains, and cellular assays. Aim 3: We will analyze the functional conservation and evolution of lbh using biologically relevant alleles of lbh isolated from cichlids with differing mandible lengths. Overal, these studies will illuminate the role of lbh in craniofacial development, disease, and evolution.

描述（由申请人提供）：颅面畸形是最常见的人类出生缺陷之一，影响1/700的出生。虽然这些缺陷背后的许多基因是已知的，但许多其他基因的身份和功能却不清楚。这项计划的首要目标是评估一个很大程度上没有特征的基因，肢芽和心脏同源基因（lbh），在斑马鱼颅面发育过程中的作用。该基因可能介导CHARGE综合征，一种神经嵴细胞（NCC）疾病，包括颅面缺陷，如小颌畸形。此外，我们已经将该基因与慈鲷科的颌骨进化相关联，慈鲷科是一种在颅面形态上表现出广泛多样性的进化模型，其中许多模仿人类面部畸形。结合，这些数据导致的假设，lbh是一种新的调节NCC和颅面发育，这将通过以下实验目标进行测试。目标1：由于缺乏关于lbh的信息，我们将首先使用整体和切片原位杂交技术，并与已知的颅面标志物进行比较，来描述整个斑马鱼面部发育过程中lbh的表达模式和细胞特异性。目的2：我们将评估调节lbh表达（morpholino敲低或mRNA过表达）对颅面骨骼的影响。初步实验表明，Lbh的耗尽导致NCC的减少和颅面骨骼的相应缺陷。具体来说，我们将确定这种缺陷的细胞机制是由于诱导失败，迁移失败，减少生存，或过早分化的NCC使用原位杂交，报告斑马鱼品系，细胞测定的组合。目标三：我们将利用从不同下颌骨长度的慈鲷中分离的lbh的生物学相关等位基因分析lbh的功能保守和进化。总之，这些研究将阐明lbh在颅面发育、疾病和进化中的作用。