Some of these reports affirmed the causes taken in the cotransfection findings that means methylation of the CpG dinucleotides

Ong et al speculated the involvement of flow-sensing cilia, as mediator of ‘‘glomerulo-tubular balance’’ in the context of kidney. Glomerulo-tubular balance refers to the phenomenon which ensures that the rate of fluid re-absorption in the proximal renal tubule is always in proportion to the rate of glomerular filtration. This requires the presence of a mechanotransducer which shall transduce the mechanical stimulus of fluid flow into signals regulating transport across ion channels. Indeed Praetorius and Spring through studies on Madin-Darby canine kidney cells, a canine kidney cell line derived from the collecting duct, reported presence of primary cilia in renal epithelium. Their study showed that this cilia is capable of sensing mechanical forces i.e, it bends when suction is applied with micropipette or if the flow rate of perfusate is increased. It also responds to the mechanical stimulus as indicated by increased calcium uptake. Further this response is not restricted to one cell. It propagates throughout the epithelial tissue by cell-cell interaction mediated by calcium signaling at cellular junctions. This was validated using gap junction permeation inhibitor heptanol which resulted in significant reduction in spread of the response. Thus it is very likely that similar to inner ear, renal epithelial cells must have a sensory system capable of sensing the variations in fluid shear stress, amplifying it and transmitting it to the intracellular cytoskeleton and thus mediating the functional regulation of membrane transport proteins. Cdh23 is a good candidate to be involved in this process. The limb expression domain of Cdh23 is very similar to the expression of another gene Papss2 reported in our metabolism related genes screen as well as to Sulf1 as reported by Zhao et al. In our MRG screen at HH26 and HH28, Papss2 is expressed in the condensing mesenchyme. Zhao et al through in situ hybridization screen in quail embryos showed that at around HH27, Sulf1 is also expressed in the condensing mesenchyme. In the context of limb skeletal development, mesenchymal cells of the developing limb bud condense and undergo chondrogenesis i.e., differentiation into cartilage fate. This cartilage anlagen serves as the template for bone formation during endochondral ossification. During this process, cartilage cells at the centre of the skeletal element undergo hypertrophic differentiation, followed by matrix secretion and apoptosis. Concomitant to this, vascular, neuronal and osteoblast invasion takes place in this zone followed by ossification which is marked by the formation of bone collar. Hypertrophic differentiation of cartilage is initiated in the middle of the anlagen and spreads outward while cartilage cells near the extremities continue to proliferate and support longitudinal growth of the developing skeletal elements. As the limb skeleton grows, the segmentation of cartilage template takes place. During this process, the incipient joint site loses cartilaginous property and forms a specialized tissue called the interzone. The interzone acts as a signaling centre and instructs the neighbouring cells of the cartilaginous template to achieve distinctive property to become articular cartilage i.e., permanent cartilage. Thus from the condensing mesenchyme of limb bud both bone and articular cartilage are formed. Whitfield referred to the primary cilium of cartilage and bone cells as the mechanosensory toggle switch. In this article Whitfield raises several important questions e.g. given the cilium of cartilage and bone is a mechanosensory device how is it toggled or what is the nature of the signal it sends and how this signaling mode is different from that of other mechanosensing systems. Cdh23 which our screen reports to be expressed in limb cartilage and from other reports is known to mediate ciliary mechanotransduction might be a good candidate in the above context. The expression patterns reported herein would thus serve as guidelines to formulate testable hypothesis in different developmental contexts. To elaborate, we would like to use some of the kidney expression patterns elucidated through this study and demonstrate how this expression information can be used in the light of the current understanding of molecular basis of kidney development to develop novel hypotheses. Kidneys are components of the genito-urinary system. The intermediate mesoderm generates the entire genito-urinary system including the kidneys. The existing literature suggests that through multiple rounds of sorting of IM cells different structural components of kidney are formed. Cells within these newly formed structures proliferate and differentiate to generate tissues that are capable of supporting the physiological function of kidney. The first morphologically distinct feature arising out of the IM is the nephric duct. As development progresses at the posterior end of the nephric duct a small tissue outgrowth, the ureteric bud, is induced. Tip of the ureteric bud emerging from the nephric duct induces the neighbouring mesenchyme to aggregate around itself and form a distinct structure called the cap mesenchyme. The cap mesenchyme is the source of all epithelial components of the nephron. Cells of the cap mesenchyme aggregate, proliferate, lose their mesenchymal properties and acquire epithelial character through mesenchymal-to-epithelial transition.

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