Delivering the Lateral Inhibition Punchline: It's All About the Timing

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science Signaling (Impact Factor: 7.65). 10/2010; 3(145):pe38. DOI: 10.1126/scisignal.3145pe38
Source: PubMed

ABSTRACT Experimental and theoretical biologists have long been fascinated with the emergence of self-organizing patterns in developing organisms, and much attention has focused on Notch-mediated lateral inhibition. Within sheets of cells that may adopt either of two possible cell fates, lateral inhibition establishes patterns through the activity of a negative intercellular feedback loop involving the receptor, Notch, and its ligands Delta or Serrate. Despite a long history of intensive study in Drosophila, where the mechanism was first described, as well as in other organisms, new work continues to yield important insights. Mathematical modeling, combined with biological analyses, has now shed light on two features of the process: how antagonistic and activating ligand-receptor interactions work together to accelerate inhibition and ensure fidelity, and how filopodial dynamics contribute to the observed pattern refinement and spacing.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular factors and tissue compartments involved in the foundation of the mammalian germline have been mainly described in the mouse so far. To find mechanisms applicable to mammals in general, we analyzed temporal and spatial expression patterns of the transcriptional repressor BLIMP1 (also known as PRDM1) and the signaling molecules BMP2 and BMP4 in perigastrulation and early neurulation embryos of the rabbit using whole-mount in situ hybridization and high-resolution light microscopy. Both BMP2 and BMP4 are expressed in annular domains at the boundary of the embryonic disc, which--in contrast to the situation in the mouse--partly belong to intraembryonic tissues. While BMP2 expression begins at (pregastrulation) stage 1 in the hypoblast, BMP4 expression commences--distinctly delayed compared to the mouse--diffusely at (pregastrulation) stage 2; from stage 3 onwards, BMP4 is expressed peripherally in hypoblast and epiblast and in the mesoderm at the posterior pole of the embryonic disc. BLIMP1 expression begins throughout the hypoblast at stage 1 and emerges in single primordial germ cell (PGC) precursors in the posterior epiblast at stage 2 and then in single mesoderm cells at positions identical to those identified by PGC-specific antibodies. These expression patterns suggest that function and chronology of factors involved in germline segregation are similar in mouse and rabbit, but higher temporal and spatial resolution offered by the rabbit demonstrates a variable role of bone morphogenetic proteins and makes "blimping" a candidate case for lateral inhibition without the need for an allantoic germ cell niche.
    Development Genes and Evolution 09/2011; 221(4):209-23. DOI:10.1007/s00427-011-0373-5 · 2.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Notch is a crucial cell signaling pathway in metazoan development. By means of cell-cell interactions, Notch signaling regulates cellular identity, proliferation, differentiation and apoptosis. Within the last decade, numerous studies have shown an important role for this pathway in the development and homeostasis of mammalian stem cell populations. Hematopoietic stem cells (HSCs) constitute a well-defined population that shows self-renewal and multi-lineage differentiation potential, with the clinically relevant capacity to repopulate the hematopoietic system of an adult organism. Here, we review the emergence, development and maintenance of HSCs during mammalian embryogenesis and adulthood, with respect to the role of Notch signaling in hematopoietic biology.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(10):1525-32. DOI:10.1038/leu.2011.127 · 9.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.
    Nature Genetics 02/2012; 44(3):348-51. DOI:10.1038/ng.1090 · 29.65 Impact Factor