Fat PCP signalling and skeletal morphogenesis

脂肪 PCP 信号传导和骨骼形态发生

• 批准号: BB/G021074/1
• 负责人: Philippa Francis-West
• 金额: $ 51.33万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG021074%2F1
• 关键词: Fat; PCP; signalling; skeletal; morphogenesis

During embryonic development the orientation of structures such as the hairs of our skin is controlled by a pathway known as the planar cell polarity (PCP) pathway. In fruitflies, where PCP signaling also controls the orientation of hairs and bristles, two pathways are known to be important: the frizzled PCP pathway and the Fat-PCP pathway. In vertebrates, including humans, the role of the frizzled PCP pathway is well known where, for example, it controls the orientation of hair cells within the inner ear enabling us to hear and the orientation of cell divisions in the kidney which allow the kidney tubules to extend and function properly. In addition, this pathway controls cell movement/shape changes allowing the extension of our body axis during development. When this does not take place properly, the neural tube (the developing spinal cord can not close). Recently, it was shown that the Fat-PCP pathway is important in not only fruitflies but in vertebrates e.g. humans and mice and also controls the orientation of structures and that defects could result in hearing defects and cystic kidney disease. By removing the function of dachsous, part of the Fat-PCP pathway in mice, we have shown that in addition to kidney and inner ear defects, the vertebrae and sternum do not develop properly. We now aim to determine how this pathway controls the morphogenesis (the shape) of the skeleton. Nothing is known about how the shape of our bones is determined, but the PCP pathways are very strong candidates to control morphogenesis. We think that PCP signalling will control the orientation of cell divisions which will allow a bone to expand in a particular direction and the movement of the skeletal cells to create the correct bone shape and we plan to investigate this idea by asking how the cells divide and change shape in developing skeletal structures when the Fat PCP pathway is not working.

在胚胎发育过程中，我们皮肤上的毛发等结构的方向是由一种称为平面细胞极性（PCP）途径的途径控制的。在果蝇中，PCP信号也控制毛发和刚毛的方向，已知有两种途径很重要：卷曲PCP途径和脂肪PCP途径。在包括人类在内的脊椎动物中，卷曲PCP通路的作用是众所周知的，例如，它控制内耳内毛细胞的方向，使我们能够听到，以及肾脏中细胞分裂的方向，使肾小管能够正常延伸和发挥功能。此外，该途径控制细胞运动/形状变化，允许我们的身体轴在发育过程中延伸。当这不发生正确的，神经管（发展中的脊髓不能关闭）。最近，研究表明，Fat-PCP途径不仅在果蝇中，而且在脊椎动物（例如人类和小鼠）中也很重要，并且还控制结构的方向，并且缺陷可能导致听力缺陷和囊性肾病。通过去除小鼠中脂肪-PCP途径的一部分dachsous的功能，我们已经表明，除了肾脏和内耳缺陷外，椎骨和胸骨也不能正常发育。我们现在的目标是确定这条通路如何控制骨骼的形态发生（形状）。我们对骨骼的形状是如何决定的一无所知，但PCP通路是控制形态发生的非常有力的候选者。我们认为PCP信号将控制细胞分裂的方向，这将允许骨骼在特定方向上扩展，以及骨骼细胞的运动以创建正确的骨骼形状，我们计划通过询问当脂肪PCP通路不起作用时细胞如何分裂和改变骨骼结构的形状来研究这一想法。

项目成果

Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate.

• DOI: 10.1371/journal.pone.0065677
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kobayashi GS;Alvizi L;Sunaga DY;Francis-West P;Kuta A;Almada BV;Ferreira SG;de Andrade-Lima LC;Bueno DF;Raposo-Amaral CE;Menck CF;Passos-Bueno MR
• 通讯作者: Passos-Bueno MR

Making and shaping endochondral and intramembranous bones.

• DOI: 10.1002/dvdy.278
• 发表时间: 2021-03
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Galea GL;Zein MR;Allen S;Francis-West P
• 通讯作者: Francis-West P

Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis.

• DOI: 10.1038/ncomms11469
• 发表时间: 2016-05-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mao Y;Kuta A;Crespo-Enriquez I;Whiting D;Martin T;Mulvaney J;Irvine KD;Francis-West P
• 通讯作者: Francis-West P