We now have a wealth of information about the molecular signals that act on cells in embryos, but how do the control systems based on these signals generate pattern and govern the timing of ...developmental events? Here, I discuss four examples to show how mathematical modeling and quantitative experimentation can give some useful answers. The examples concern the Bicoid gradient in the early Drosophila embryo, the dorsoventral patterning of a frog embryo by bone morphogenetic protein signals, the auxin-mediated patterning of plant meristems, and the Notch-dependent somite segmentation clock.
The lining of the intestine is renewed at an extraordinary rate, outpacing all other tissues in the vertebrate body. The renewal process is neatly organized in space, so that the whole production ...line, from the ever-youthful stem cells to their dying, terminally differentiated progeny, is laid out to view in histological sections. A flurry of recent papers has clarified the key regulatory signals and brought us to the point where we can begin to give a coherent account, for at least one tissue, of how these signals collaborate to organize the architecture and behaviour of a stem-cell system.
Each of the sensory patches in the epithelium of the inner ear is a mosaic of hair cells and supporting cells. Notch signalling is thought to govern this pattern of differentiation through lateral ...inhibition. Recent experiments in the chick suggest, however, that Notch signalling also has a prior function - inductive rather than inhibitory - in defining the prosensory patches from which the differentiated cells arise. Several Notch ligands are expressed in each patch, but their individual roles in relation to the two functions of Notch signalling are unclear. We have used a Cre-LoxP approach to knock out two of these ligands, Delta1 (Dll1) and Jagged1 (Jag1), in the mouse ear. In the absence of Dll1, auditory hair cells develop early and in excess, in agreement with the lateral inhibition hypothesis. In the absence of Jag1, by contrast, the total number of these cells is strongly reduced, with complete loss of cochlear outer hair cells and some groups of vestibular hair cells, indicating that Jag1 is required for the prosensory inductive function of Notch. The number of cochlear inner hair cells, however, is almost doubled. This correlates with loss of expression of the cell cycle inhibitor p27(Kip1) (Cdkn1b), suggesting that signalling by Jag1 is also needed to limit proliferation of prosensory cells, and that there is a core part of this population whose prosensory character is established independently of Jag1-Notch signalling. Our findings confirm that Notch signalling in the ear has distinct prosensory and lateral-inhibitory functions, for which different ligands are primarily responsible.
Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death of adults in the USA and worldwide. While environmental factors such as smoking and air pollution are major ...contributors to COPD, pediatric respiratory disease and more specifically early childhood wheezing are frequent predisposing factors. It is therefore possible that aggressive prevention and treatment of childhood respiratory illness may modify adult COPD risk. This article reviews some of the physiological factors that may explain the pediatric origins of childhood lung disease. One such factor is the “tracking” of normal lung function which occurs with growth. The maximal expiratory flow volume (MEFV) curve is an ideally suited tool to monitor tracking of airway function over the lifespan, as its relative effort independence makes it highly reliable. Study of the MEFV curve has demonstrated that individuals with similar lung volumes can have large differences in maximal flows, reflecting a disconnection between airway and lung growth (“dysanapsis”). Less than average airway size due to dysanaptic airway growth or airway remodeling may be independent risk factors for the development of COPD and the asthma/COPD overlap syndrome in adult life. There are intriguing early data suggesting that perhaps at least some of this risk is modifiable by improving asthma control with inhaled corticosteroids and minimizing asthma exacerbations.
Background & Aims Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to ...confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Methods Transgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ERT2 ). Results Notch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4+ , Lgr5+ , and Ascl2+ ). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway–deficient gut. Conclusions Notch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice.
Lateral inhibition mediated by Notch is thought to generate the mosaic of hair cells and supporting cells in the inner ear, but the effects of the activated Notch protein itself have never been ...directly tested. We have explored the role of Notch signalling by transiently overexpressing activated Notch (NICD) in the chick otocyst. We saw two contrasting consequences, depending on the time and site of gene misexpression: (1) inhibition of hair-cell differentiation within a sensory patch; and (2) induction of ectopic sensory patches. We infer that Notch signalling has at least two functions during inner ear development. Initially, Notch activity can drive cells to adopt a prosensory character, defining future sensory patches. Subsequently, Notch signalling within each such patch mediates lateral inhibition, restricting the proportion of cells that differentiate as hair cells so as to generate the fine-grained mixture of hair cells and supporting cells.
Notch signalling by the ligand Delta-like 4 (Dll4) is essential for normal vascular remodelling, yet the precise way in which the pathway influences the behaviour of endothelial cells remains a ...mystery. Using the embryonic zebrafish, we show that, when Dll4-Notch signalling is defective, endothelial cells continue to migrate and proliferate when they should normally stop these processes. Artificial overactivation of the Notch pathway has opposite consequences. When vascular endothelial growth factor (Vegf) signalling and Dll4-Notch signalling are both blocked, the endothelial cells remain quiescent. Thus, Dll4-Notch signalling acts as an angiogenic ;off' switch by making endothelial cells unresponsive to Vegf.
A tribute to George Polgar, M.D Allen, Julian Lewis
Pediatric investigation,
December 2019, Volume:
3, Issue:
4
Journal Article
Peer reviewed
Open access
During World War II, his family was persecuted by the German‐aligned Hungarian government and stripped of its vast vineyards, a large wine‐making operation and businesses that included a bank and law ...firm. While at CHOP, he performed pioneering research in neonatal respiratory physiology and measurement of lung mechanics with colleagues at the University of Pennsylvania. ...he is perhaps best known for his meticulous development of methods for lung function testing in infants and children, and the compilation of reference pediatric values, resulting in the authorship with Varuni Promadhat in 1971 of their book considered to be a classic in the field, “Pulmonary function testing in children:
Notch signalling is well-known to mediate lateral inhibition in inner ear sensory patches, so as to generate a balanced mixture of sensory hair cells and supporting cells. Recently, however, we have ...found that ectopic Notch activity at an early stage can induce the formation of ectopic sensory patches. This suggests that Notch activity may have two different functions in normal ear development, acting first to promote the formation of the prosensory patches, and then later to regulate hair-cell production within the patches. The Notch ligand Serrate1 (Jag1 in mouse and humans) is expressed in the patches from an early stage and may provide Notch activation during the prosensory phase. Here, we test whether Notch signalling is actually required for prosensory patch development. When we block Notch activation in the chick embryo using the gamma-secretase inhibitor DAPT, we see a complete loss of prosensory epithelial cells in the anterior otocyst, where they are diverted into a neuroblast fate via failure of Delta1-dependent lateral inhibition. The cells of the posterior prosensory patch remain epithelial, but expression of Sox2 and Bmp4 is drastically reduced. Expression of Serrate1 here is initially almost normal, but subsequently regresses. The patches of sensory hair cells that eventually develop are few and small. We suggest that, in normal development, factors other than Notch activity initiate Serrate1 expression. Serrate1, by activating Notch, then drives the expression of Sox2 and Bmp4, as well as expression of the Serrate1 gene itself. The positive feedback maintains Notch activation and thereby preserves and perhaps extends the prosensory state, leading eventually to the development of normal sensory patches.
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