Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs. Notch activity affects the implementation of differentiation, proliferation, and apoptotic programs, providing a general developmental tool to influence organ formation and morphogenesis.

http://science.sciencemag.org/content/sci/284/5415/770.full.pdf

Notch Signaling: Cell Fate Control and Signal Integration in Development

Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.

/pdf/matrix-metalloproteinases-and-the-regulation-of-tissue-3wk0irdopd.pdf

Matrix metalloproteinases and the regulation of tissue remodelling

Development of the body plan is controlled by large networks of regulatory genes. A gene regulatory network that controls the specification of endoderm and mesoderm in the sea urchin embryo is summarized here. The network was derived from large-scale perturbation analyses, in combination with computational methodologies, genomic data, cis-regulatory analysis, and molecular embryology. The network contains over 40 genes at present, and each node can be directly verified at the DNA sequence level by cis-regulatory analysis. Its architecture reveals specific and general aspects of development, such as how given cells generate their ordained fates in the embryo and why the process moves inexorably forward in developmental time.

https://science.sciencemag.org/content/sci/295/5560/1669.full.pdf

A Genomic Regulatory Network for Development

Analysis of Development Edited by Prof Benjamin H Willier, Prof Paul A Weiss and Prof Viktor Hamburger Pp xii + 735 (Philadelphia and London: W B Saunders Company, 1955) 105s

Mechanisms of Development

Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology.

Cell-cell interactions are thought to regulate the differential specification of secondary mesenchyme cells (SMCs) and endoderm in the sea urchin embryo. The molecular bases of these interactions, however, are unknown. We have previously shown that the sea urchin homologue of the LIN-12/Notch receptor, LvNotch, displays dynamic patterns of expression within both the presumptive SMCs and endoderm during the blastula stage, the time at which these two cell types are thought to be differentially specified (Sherwood, D. R. and McClay, D. R. (1997) Development 124, 3363–3374). The LIN-12/Notch signaling pathway has been shown to mediate the segregation of numerous cell types in both invertebrate and vertebrate embryos. To directly examine whether LvNotch signaling has a role in the differential specification of SMCs and endoderm, we have overexpressed activated and dominant negative forms of LvNotch during early sea urchin development. We show that activation of LvNotch signaling increases SMC specification, while loss or reduction of LvNotch signaling eliminates or significantly decreases SMC specification. Furthermore, results from a mosaic analysis of LvNotch function as well as endogenous LvNotch expression strongly suggest that LvNotch signaling acts autonomously within the presumptive SMCs to mediate SMC specification. Finally, we demonstrate that the expansion of SMCs seen with activation of LvNotch signaling comes at the expense of presumptive endoderm cells, while loss of SMC specification results in the endoderm expanding into territory where SMCs usually arise. Taken together, these results offer compelling evidence that LvNotch signaling directly specifies the SMC fate, and that this signaling is critical for the differential specification of SMCs and endoderm in the sea urchin embryo.

LvNotch signaling mediates secondary mesenchyme specification in the sea urchin embryo

https://sites.duke.edu/sherwoodlab/files/2012/12/pdf16.pdf

FOS-1 Promotes Basement-Membrane Removal during Anchor-Cell Invasion in C. elegans

https://sites.duke.edu/sherwoodlab/files/2012/12/pdf18.pdf

Anchor cell invasion into the vulval epithelium in C. elegans.

The basement membrane is a dense, highly cross-linked, sheet-like extracellular matrix that underlies all epithelia and endothelia in multicellular animals. During development, leukocyte trafficking, and metastatic disease, cells cross the basement membrane to disperse and enter new tissues. Based largely on in vitro studies, cells have been thought to use proteases to dissolve and traverse this formidable obstacle. Surprisingly, recent in vivo studies have uncovered a remarkably diverse range of cellular- and tissue-level strategies beyond proteolysis that cells use to navigate through the basement membrane. These fascinating and unexpected mechanisms have increased our understanding of how cells cross this matrix barrier in physiological and disease settings.

/pdf/traversing-the-basement-membrane-in-vivo-a-diversity-of-2fmnntjgyk.pdf

Traversing the basement membrane in vivo: A diversity of strategies

The C.elegans anchor cell is a model for cellular invasion through the basement membrane. Now netrin (UNC-6) is found to polarize the actin regulators Ena/VASP and PtdIns (4,5)P2 towards the basement membrane to promote anchor cell invasion. Despite their profound importance in the development of cancer, the extracellular cues that target cell invasion through basement membrane barriers remain poorly understood1. A central obstacle has been the difficulty of studying the interactions between invading cells and basement membranes in vivo2,3. Using the genetically and visually tractable model of Caenorhabditis elegans anchor cell (AC) invasion, we show that UNC-6 (netrin) signalling, a pathway not previously implicated in controlling cell invasion in vivo, is a key regulator of this process. Site of action studies reveal that before invasion, localized UNC-6 secretion directs its receptor, UNC-40, to the plasma membrane of the AC, in contact with the basement membrane. There, UNC-40 polarizes a specialized invasive membrane domain through the enrichment of actin regulators, F-actin and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Cell ablation experiments indicate that UNC-6 promotes the formation of invasive protrusions from the AC that break down the basement membrane in response to a subsequent vulval cue. Together, these results characterize an invasive membrane domain in vivo, and reveal a role for UNC-6 (netrin) in polarizing this domain towards its basement membrane target.

/pdf/unc-6-netrin-orients-the-invasive-membrane-of-the-anchor-1lpc3e75zw.pdf

David R. Sherwood

Papers

LvNotch signaling mediates secondary mesenchyme specification in the sea urchin embryo

FOS-1 Promotes Basement-Membrane Removal during Anchor-Cell Invasion in C. elegans

Anchor cell invasion into the vulval epithelium in C. elegans.

Traversing the basement membrane in vivo: A diversity of strategies

UNC-6 (netrin) orients the invasive membrane of the anchor cell in C. elegans.