Cells & Development最新文献

The current dogma in cancer biology contends that cancer is an identity problem: mutations in a cell's DNA cause it to "go rogue" and proliferate out of control. However, this largely ignores the role of cell-cell interaction and fails to explain phenomena such as cancer reversion, the existence of cancers without mutations, and foreign-body carcinogenesis. In this proof-of-concept paper, we draw on criminology to propose that cancer may alternatively be conceptualized as a relational problem: Although a cell's genetics is essential, the influence of its interaction with other cells is equally important in determining its phenotype. We create a simple agent-based network model of interactions among normal and cancer cells to demonstrate this idea. We find that both high mutation rates and low levels of connectivity among cells can promote oncogenesis. Viewing cancer as a breakdown in communication networks among cells in a tissue complements the gene-centric paradigm nicely and provides a novel perspective for understanding and treating cancer.

In vertebrates, the three orthogonal body axes, anteroposterior (AP), dorsoventral (DV) and left-right (LR) are determined at gastrula and neurula stages by the Spemann-Mangold organizer and its equivalents. A common feature of AP and DV axis formation is that an evolutionary conserved interplay between growth factors (Wnt, BMP) and their extracellular antagonists (e.g. Dkk1, Chordin) creates signaling gradients for axial patterning. Recent work showed that LR patterning in Xenopus follows the same principle, with R-spondin 2 (Rspo2) as an extracellular FGF antagonist, which creates a signaling gradient that determines the LR vector. That a triad of anti-FGF, anti-BMP, and anti-Wnt governs LR, DV, and AP axis formation reveals a unifying principle in animal development. We discuss how cross-talk between these three signals confers integrated AP-DV-LR body axis patterning underlying developmental robustness, size scaling, and harmonious regulation. We propose that Urbilateria featured three orthogonal body axes that were governed by a Cartesian coordinate system of orthogonal Wnt/AP, BMP/DV, and FGF/LR signaling gradients.

Podoplanin is a vital molecule which plays an integral part in the regulation of development, immunity, and cancer. Expression of Podoplanin is detected at different early developmental stages of mammalian embryo, and it functions to modulate morphogenesis of various organ systems. In experimental animal models of different genetic backgrounds, absence of Podoplanin results in either embryonic lethality or immediate death upon birth, suggesting the importance of the gene in early developmental processes. This review discusses the gene and protein structure of Podoplanin; and elucidates various functions of Podoplanin in different systems, including central nervous system as well as respiratory, lymphatic, and cardiovascular systems.

Development is a self-organized process that builds on cells and their interactions. Cells are heterogeneous in gene expression, growth, and division; yet how development is robust despite such heterogeneity is a fascinating question. Here, we review recent progress on this topic, highlighting how developmental robustness is achieved through self-organization. We will first discuss sources of heterogeneity, including stochastic gene expression, heterogeneity in growth rate and direction, and heterogeneity in division rate and precision. We then discuss cellular mechanisms that buffer against such noise, including Paf1C- and miRNA-mediated denoising, spatiotemporal growth averaging and compensation, mechanisms to improve cell division precision, and coordination of growth rate and developmental timing between different parts of an organ. We also discuss cases where such heterogeneity is not buffered but utilized for development. Finally, we highlight potential directions for future studies of noise and developmental robustness.

Neural induction by cell-cell signaling was discovered a century ago by the organizer transplantations of Spemann and Mangold in amphibians. Spemann later found that early dorsal blastopore lips induced heads and late organizers trunk-tail structures. Identifying region-specific organizer signals has been a driving force in the progress of animal biology. Head induction in the absence of trunk is designated archencephalic differentiation. Two specific head inducers, Cerberus and Insulin-like growth factors (IGFs), that induce archencephalic brain but not trunk-tail structures have been described previously. However, whether these two signals interact with each other had not been studied to date and was the purpose of the present investigation. It was found that Cerberus, a multivalent growth factor antagonist that inhibits Nodal, BMP and Wnt signals, strongly cooperated with IGF2, a growth factor that provides a positive signal through tyrosine kinase IGF receptors that activate MAPK and other pathways. The ectopic archencephalic structures induced by the combination of Cerberus and IGF2 are of higher frequency and larger than either one alone. They contain brain, a cyclopic eye and multiple olfactory placodes, without trace of trunk structures such as notochord or somites. A dominant-negative secreted IGF receptor 1 blocked Cerberus activity, indicating that endogenous IGF signals are required for ectopic brain formation. In a sensitized embryonic system, in which embryos were depleted of β-catenin, IGF2 did not by itself induce neural tissue while in combination with Cerberus it greatly enhanced formation of circular brain structures expressing the anterior markers Otx2 and Rx2a, but not spinal cord or notochord markers. The main conclusion of this work is that IGF provides a positive signal initially uniformly expressed throughout the embryo that potentiates the effect of an organizer-specific negative signal mediated by Cerberus. The results are discussed in the context of the history of neural induction.