RSK2 is a modulator of craniofacial development

The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked monogenic disease associating severe learning deficit andassociated to typical facial and digital abnormalities and skeletal changes. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized. In this study we explore, through X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, an animal model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report in these mutants the occurrence of a surpernumerary tooth mesial to the first molar. This highly penetrant phenotype is considered as a remnant of evolutionary lost teeth. This possibly leads to the significant reduction of the maxillary diastema. Abnormalities of molar shape were almost restricted to the mesial part of both upper and lower first molars (M1). We also report an expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) at various stages of odontogenesis in wild-type (WT) mice. Rsk2 was mainly expressed in the mesenchymal, neural crest derived compartment, correlating with proliferative areas of the developing teeth and consistent with a biological function of RSK2 in cell cycle control and cell growth, which when invalidated could be responsible for the dental phenotype. In an attempt to unravel the molecular pathways involved in the genesis of these dental defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars, and further demonstrated a misregulation of selected genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro.RSK2基因与Coffin-Lowry综合征（Coffin-Lowry syndrome）相关，该疾病为X连锁单基因遗传病，患者会出现严重学习障碍，同时伴有典型的面部、指（趾）异常及骨骼改变。目前针对这种罕见疾病中出现的颅面与牙齿异常的特征描述仍较为匮乏。本研究借助X射线显微断层扫描（X-Ray microtomographic）技术，对Coffin-Lowry综合征的动物模型——Rsk2基因敲除小鼠，以及三重Rsk1、2、3基因敲除突变体中存在的可变颅面畸形与牙齿异常展开了探究。本研究报道了在上述突变体中，第一磨牙近中侧出现多生牙的现象。该表型具有高外显率，被认为是进化过程中丢失牙齿的残留结构，且可能导致上颌牙间隙显著缩小。磨牙形态异常几乎仅局限于上下颌第一磨牙（M1）的近中区域。此外，本研究还对野生型（wild-type, WT）小鼠牙发育不同阶段的4种Rsk基因（Rsk1、2、3和4）开展了表达分析：Rsk2主要在间充质、神经嵴来源的细胞区域表达，与发育中牙齿的增殖区域具有相关性，这与RSK2在细胞周期调控与细胞生长中的生物学功能相符，而RSK2功能失活可能是导致牙齿表型异常的原因。为阐明此类牙齿缺陷发生的分子通路，本研究对野生型与Rsk2-/Y小鼠的下颌磨牙开展了比较转录组（transcriptomic）分析（DNA微阵列，DNA microarray），并通过在体外培养的磨牙牙胚中使用Rsk2短发夹RNA（shRNA）基因敲低策略，进一步验证了部分候选基因的表达失调。