Warner Dennis R, Mukhopadhyay Partha, Brock Guy, Webb Cindy L, Michele Pisano M, Greene Robert M
Department of Molecular, Cellular, and Craniofacial Biology, University of Louisville Birth Defects Center, Louisville, Kentucky, USA.
Dev Growth Differ. 2014 Aug;56(6):434-47. doi: 10.1111/dgd.12140. Epub 2014 May 22.
Clefts of the lip and palate are thought to be caused by genetic and environmental insults but the role of epigenetic mechanisms underlying this common birth defect are unknown. We analyzed the expression of over 600 microRNAs in the murine medial nasal and maxillary processes isolated on GD10.0-GD11.5 to identify those expressed during development of the upper lip and analyzed spatial expression of a subset. A total of 142 microRNAs were differentially expressed across gestation days 10.0-11.5 in the medial nasal processes, and 66 in the maxillary processes of the first branchial arch with 45 common to both. Of the microRNAs exhibiting the largest percent increase in both facial processes were five members of the Let-7 family. Among those with the greatest decrease in expression from GD10.0 to GD11.5 were members of the microRNA-302/367 family that have been implicated in cellular reprogramming. The distribution of expression of microRNA-199a-3p and Let-7i was determined by in situ hybridization and revealed widespread expression in both medial nasal and maxillary facial process, while that for microRNA-203 was much more limited. MicroRNAs are dynamically expressed in the tissues that form the upper lip and several were identified that target mRNAs known to be important for its development, including those that regulate the two main isoforms of p63 (microRNA-203 and microRNA-302/367 family). Integration of these data with corresponding proteomic datasets will lead to a greater appreciation of epigenetic regulation of lip development and provide a better understanding of potential causes of cleft lip.
唇腭裂被认为是由遗传和环境因素导致的，但这种常见出生缺陷背后的表观遗传机制尚不清楚。我们分析了在妊娠第10.0天至11.5天分离的小鼠内侧鼻突和上颌突中600多种微小RNA的表达，以确定在上唇发育过程中表达的那些微小RNA，并分析了其中一部分的空间表达。在内侧鼻突中，共有142种微小RNA在妊娠第10.0天至11.5天期间差异表达，在第一鳃弓的上颌突中有66种，两者共有45种。在两个面部突起中表达增加百分比最大的微小RNA中有5个是Let-7家族的成员。在从妊娠第10.0天到11.5天表达下降最大的微小RNA中有微小RNA-302/367家族的成员，它们与细胞重编程有关。通过原位杂交确定了微小RNA-199a-3p和Let-7i的表达分布，结果显示它们在内侧鼻突和上颌面部突起中均广泛表达，而微小RNA-203的表达则更为局限。微小RNA在形成上唇的组织中动态表达，并且鉴定出了几种靶向已知对其发育重要的mRNA的微小RNA，包括那些调节p63两种主要异构体的微小RNA（微小RNA-203和微小RNA-302/367家族）。将这些数据与相应的蛋白质组数据集整合，将有助于更深入地了解唇发育的表观遗传调控，并更好地理解唇裂的潜在原因。
