Cilia functions in development

Recent advances in developmental genetics and human disease gene cloning have highlighted the essential roles played by cilia in developmental cell fate decisions, left-right asymmetry, and the pathology of human congenital disorders. Hedgehog signaling in sensory cilia illustrates the importance of trafficking receptors to the cilia membrane (Patched and Smoothened) and the concept of cilia 'gatekeepers' that restrict entry and egress of cilia proteins (Suppressor of fused: Gli complexes). Cilia-driven fluid flow in the embryonic node highlights the role of motile cilia in both generation and detection of mechanical signals in development. In this brief review I select examples of recent studies that have clarified and consolidated our understanding of the role of cilia in development.     

Cilia in vertebrate development and disease

Through the combined study of model organisms, cell biology, cell signaling and medical genetics we have significantly increased our understanding of the structure and functions of the vertebrate cilium. This ancient organelle has now emerged as a crucial component of certain signaling and sensory perception pathways in both developmental and homeostatic contexts. Here, we provide a snapshot of the structure, function and distribution of the vertebrate cilium and of the pathologies that are associated with its dysfunction.     

Cilia and coordination of signaling networks during heart development

Primary cilia are unique sensory organelles that coordinate a wide variety of different signaling pathways to control cellular processes during development and in tissue homeostasis. Defects in function or assembly of these antenna-like structures are therefore associated with a broad range of developmental disorders and diseases called ciliopathies. Recent studies have indicated a major role of different populations of cilia, including nodal and cardiac primary cilia, in coordinating heart development, and defects in these cilia are associated with congenital heart disease. Here, we present an overview of the role of nodal and cardiac primary cilia in heart development.     

Cilia and coordination of signaling networks during heart development

Primary cilia are unique sensory organelles that coordinate a wide variety of different signaling pathways to control cellular processes during development and in tissue homeostasis. Defects in function or assembly of these antenna-like structures are therefore associated with a broad range of developmental disorders and diseases called ciliopathies. Recent studies have indicated a major role of different populations of cilia, including nodal and cardiac primary cilia, in coordinating heart development, and defects in these cilia are associated with congenital heart disease. Here, we present an overview of the role of nodal and cardiac primary cilia in heart development.     

纤毛及纤毛相关疾病研究进展

纤毛是一种以细胞微管为主形成的突出于细胞表面的结构,分布于哺乳动物体内的大多数细胞。近年来研究发现,很多人类疾病都与纤毛结构、长度的失调相关,所以有关纤毛的研究是目前研究的热点领域。越来越多的证据证明,纤毛除了提供流体推动力参与细胞的运动功能之外,还具有信号传导的功能,在细胞生命活动的各个方面发挥着多种关键作用。它参与调控细胞生理活动、增殖与分化以及动物个体发育。因此,深入地探索纤毛调控机理对基础生物学理论的发展和人类纤毛相关疾病的攻克有重要意义。该文简要介绍了纤毛的结构、组装与解聚的机制、参与信号传导的功能以及纤毛缺陷同人类疾病的关系。     

Extracellular matrix and the mechanics of large artery development

The large, elastic arteries, as their name suggests, provide elastic distention and recoil during the cardiac cycle in vertebrate animals. The arteries are distended from the pressure of ejecting blood during the active contraction of the left ventricle (LV) during systole and recoil to their original dimensions during relaxation of the LV during diastole. The cyclic distension occurs with minimal energy loss, due to the elastic properties of one of the major structural extracellular matrix (ECM) components, elastin. The maximum distension is limited to prevent damage to the artery by another major ECM component, collagen. The mix of ECM components in the wall largely determines the passive mechanical behavior of the arteries and the subsequent load on the heart during systole. While much research has focused on initial artery formation, there has been less attention on the continuing development of the artery to produce the mature composite wall complete with endothelial cells (ECs), smooth muscle cells (SMCs), and the necessary mix of ECM components for proper cardiovascular function. This review focuses on the physiology of large artery development, including SMC differentiation and ECM production. The effects of hemodynamic forces and ECM deposition on the evolving arterial structure and function are discussed. Human diseases and mouse models with genetic mutations in ECM proteins that affect large artery development are summarized. A review of constitutive models and growth and remodeling theories is presented, along with future directions to improve understanding of ECM and the mechanics of large artery development.     

Nuclear mechanics in differentiation and development

The nucleus is by far one of the stiffest organelles within cells of higher eukaryotes. Its mechanical properties are determined by contributions from the nuclear lamina and chromatin. Together they allow a viscoelastic response of the nucleus to applied stresses, where the lamina is thought to behave as an elastic shell, while the nucleoplasm contributes as a largely viscous material. Nuclear mechanics changes during differentiation and development. Altered nuclear mechanics reflects but might also influence global re-arrangements in chromatin architecture, which take place when cells commit themselves into distinct lineages. Thus it is likely that the mechanical characteristics of nuclei significantly contribute to proper differentiation.     

The fluid mechanics of bolus ejection from the oral cavity

The squeezing action of the tongue against the palate provides driving forces to propel swallowed material out of the mouth and through the pharynx. Transport in respose to these driving forces, however, is dependent on the material properties of the swallowed bolus. Given the complex geometry of the oral cavity and the unsteady nature of this process, the mechanics governing the oral phase of swallowing are not well understood. In the current work, the squeezing flow between two approaching parallel plates is used as a simplified mathematical model to study the fluid mechanics of bolus ejection from the oral cavity. Driving forces generated by the contraction of intrinsic and extrinsic lingual muscles are modeled as a spatially uniform pressure applied to the tongue. Approximating the tongue as a rigid body, the motion of tongue and fluid are then computed simultaneously as a function of time. Bolus ejection is parameterized by the time taken to clear half the bolus from the oral cavity, t_1/2. We find that t_1/2 increases with increased viscosity and density and decreases with increased applied pressure. In addition, for low viscosity boluses (μapproximately 1000 cP), viscosity dominates. A transition region between these two regimes is found in which both properties affect the solution characteristics. The relationship of these results to the assessment and treatment of swallowing disorders is discussed.     

Vascular fluid mechanics, the arterial wall, and atherosclerosis.

Atherosclerosis, a disease of large- and medium-size arteries, is the chief cause of death in the United States and in most of the western world. Severe atherosclerosis interferes with blood flow; however, even in the early stages of the disease, i.e. during atherogenesis, there is believed to be an important relationship between the disease processes and the characteristics of the blood flow in the arteries. Atherogenesis involves complex cascades of interactions among many factors. Included in this are fluid mechanical factors which are believed to be a cause of the highly focal nature of the disease. From in vivo studies, there is evidence of hemodynamic influences on the endothelium, on intimal thickening, and on monocyte recruitment. In addition, cell culture studies have demonstrated the important effect of a cell's mechanical environment on structure and function. Most of this evidence is for the endothelial cell, which is believed to be a key mediator of any hemodynamic effect, and it is now well documented that cultured endothelial monolayers, in response to a fluid flow-imposed laminar shear stress, undergo a variety of changes in structure and function. In spite of the progress in recent years, there are many areas in which further work will provide important new information. One of these is in the engineering of the cell culture environment so as to make it more physiologic. Animal studies also are essential in our efforts to understand atherogenesis, and it is clear that we need better information on the pattern of the disease and its temporal development in humans and animal models, as well as the specific underlying biologic events.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of surrounding tissue on vessel fluid and solid mechanics

There is no doubt that atherosclerosis is one of the most important health problems in the Western Societies. It is well accepted that atherosclerosis is associated with abnormal stress and strain conditions. A compelling observation is that the epicardial arteries develop atherosclerosis while the intramural arteries do not. Atherosclerotic changes involving the epicardial portion of the coronary artery stop where the artery penetrates the myocardium. The objective of the present study is to understand the fluid and solid mechanical differences between the two types of vessels. A finite element analysis was employed to investigate the effect of external tissue contraction on the characteristics of pulsatile blood flow and the vessel wall stress distribution. The sequential coupling of fluid-solid interaction (FSI) revealed that the changes of flow velocity and wall shear stress, in response to cyclical external loading, appear less important than the circumferential stress and strain reduction in the vessel wall under the proposed boundary conditions. These results have important implications since high stresses and strains can induce growth, remodeling, and atherosclerosis; and hence we speculate that a reduction of stress and strain may be atheroprotective. The importance of FSI in deformable vessels with pulsatile flow is discussed and the fluid and solid mechanics differences between epicardial and intramural vessels are highlighted.     

Cilia,calcium and the basis of left-right asymmetry

The clockwise rotation of cilia in the developing mammalian embryo drives a leftward flow of liquid; this genetically regulated biophysical force specifies left-right asymmetry of the mammalian body. How leftward flow is interpreted and information propagated to other tissues is the subject of debate. Four recent papers have shed fresh light on the possible mechanisms.     

Cilia in the fetal and neonatal canine retina

Cilia in the canine retina were examined at 40, 46 and 50 days of gestation and at birth by scanning electron microscopy, transmission electron microscopy, and by the freeze-fracture technique. Cilia were similar in all age groups examined. Scanning electron micrographs showed them to be smooth-surfaced conical to tubular extensions arising from putative photoreceptor inner segments. Cilia when freeze-fractured contained variable numbers of circumferential rows of 10 nm P-face particles: these constitute the ciliary necklace. Transmission electron micrographs showed the ciliary membrane to contain electron-dense beads which corresponded to the ciliary necklace seen in freeze-fracture replicas. The ciliary necklace identified in the developing canine retina was similar to those found in other types of motile and sensory cilia.