Roles of miRNAs in dermal bone development

描述（由申请人提供）：颅面异常是一些最常见的结构性出生缺陷，通常与发育障碍，脑成熟异常，听力损失，呼吸，进食和语言相关的功能问题有关。颅骨形成和重塑受损可导致许多颅面异常，而颅骨骨骼结构发育的发病机制仍知之甚少。我们的初步数据表明，microRNAs （miRNAs）是一类新的丰富的基因调控分子，在颅膜内骨发育中具有重要作用。这是通过Dicer的条件等位基因（一种将前体加工成功能性mirna所需的酶）和Wnt1::Cre构建体揭示的，Wnt1::Cre构建体是来自背神经管的细胞的特异性构建体，包括颅神经嵴细胞，这些细胞产生了大多数面部、颅骨和颌骨。由此产生的表型包括颅软骨减少，面部骨骼完全缺失和广泛异位的头软骨，表明分化表型改变。由于上述许多人类颅面疾病的范围从轻微到非常严重，更好地了解正常和异常的膜内骨发育将对包括幼儿在内的许多人类颅面疾病、疾病和损伤的未来诊断、治疗和预防的进步至关重要。本项目的长期目标是了解正常和异常情况下颅骨发育和形态发生的机制。在本提案中，我们的目标是研究几个先前鉴定的颅真皮骨特异性候选mirna的生物学作用。该分析结果将用于开始更全面的生物信息学检查，以确定mirna如何控制膜内成骨细胞分化。

DESCRIPTION (provided by applicant): Craniofacial abnormalities are some of the most common structural birth defects that are often associated with developmental disabilities, abnormalities to brain maturation, hearing loss, functional problems related to breathing, eating, and speech. Impaired cranial bone formation and remodeling can contribute to many of these craniofacial abnormalities and pathogenesis of the developing cranial skeletal structures still remains poorly understood. Our preliminary data suggests that, microRNAs (miRNAs) are a new class of abundant gene regulatory molecules, have an important role in cranial intramembranous bone development. This was revealed with a conditional allele of Dicer, an enzyme required for processing of precursors into functional miRNAs, and a Wnt1::Cre construct that is specific to cells originating from the dorsal neural tube, including cranial neural crest cells, which give rise to most of the facial, calvarial and jawbones. The resulting phenotype includes reduced cranial cartilages, completely absent facial bones and extensive ectopic calvarial cartilage suggesting an altered differentiation phenotype. As many of the craniofacial human diseases mentioned above range from mild to very severe, better understanding of both normal and abnormal intramembranous bone development will be will be paramount to the advancement of future diagnoses, treatments and prevention of many craniofacial disorders, diseases and injuries in the human population, including young children. The long-term objective of this project is to understand mechanisms of the cranial bone development and morphogenesis in normal and abnormal conditions. In this proposal, we aim to investigate the biological roles for several previously identified cranial dermal bone-specific candidate miRNAs. The results of this analysis will be used to start a more comprehensive bioinformatics examination to establish how miRNAs control intramembranous osteoblast differentiation. Project Narrative: Each year thousands of children are born with mild to severe craniofacial diseases related to abnormal cranial bone biology. We found that microRNAs, an interesting class of regulatory molecules, are required for normal cranial bone formation. We believe that that learning about functions of these molecules using sophisticated bioinformatics tools will help us understand the mechanism governing normal cranial bone biology and allow us to develop ways to diagnose, prevent and treat various bone-related craniofacial syndromes in the future.