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.
"The expression of these activators maintains neural competency in groups of otherwise equipotential cells, the proneural clusters (PNCs). This broad expression of Ato/ASC is later refined by the HES repressors in a process called lateral inhibition –, during which the presumptive R8/SOP activates Notch to elicit HES expression in all other cells of the PNC. The HES repressors then antagonize Ato/ASC, thereby ensuring the specification (birth) of a single R8/SOP from each PNC, which is critical for proper structure and patterning of the eye and bristles. "
[Show abstract][Hide abstract] ABSTRACT: Drosophila Enhancer of split M8, an effector of Notch signaling, is regulated by protein kinase CK2. The phosphatase PP2A is thought to play an opposing (inhibitory) role, but the identity of the regulatory subunit was unknown. The studies described here reveal a role for the PP2A regulatory subunit widerborst (wdb) in three developmental contexts; the bristle, wing and the R8 photoreceptors of the eye. wdb overexpression elicits bristle and wing defects akin to reduced Notch signaling, whereas hypomorphic mutations in this PP2A subunit elicit opposite effects. We have also evaluated wdb functions using mutations in Notch and E(spl) that affect the eye. We find that the eye and R8 defects of the well-known Nspl mutation are enhanced by a hypomorphic allele of wdb, whereas they are strongly rescued by wdb overexpression. Similarly, ectopic wdb rescues the eye and R8 defects of the E(spl)D mutation, which affects the m8 gene. In addition, wdb overexpression also rescues the bristle defects of ectopically expressed M8, or the eye and R8 defects of its CK2 phosphomimetic variant M8-S159D. The latter finding suggests that PP2A may target M8 at highly conserved residues in the vicinity of the CK2 site, whose phosphorylation controls repression of Atonal and the R8 fate. Together, the studies identify PP2A-Wdb as a participant in Notch signaling, and suggest that M8 activity is controlled by phosphorylation and dephosphorylation. The conservation of the phosphorylation sites between Drosophila E(spl) and the HES/HER proteins from mammals, reptiles, amphibians, birds and fish raises the prospect that this mode of regulation is widespread.
PLoS ONE 07/2014; 9(7):e101884. DOI:10.1371/journal.pone.0101884 · 3.23 Impact Factor
"However, our cell autonomy results suggest that SMP-1 functions with PLX-1 in cis to regulate subcellular localization of PLX-1. It has been reported that some transmembrane ligands, including Sema6A, function in the same cells as their receptors to inhibit receptor activation by competing with the trans-expressed ligands or through unknown mechanisms (Axelrod, 2010; Haklai-Topper et al., 2010; Yaron and Sprinzak, 2012). Our results are a demonstration that a semaphorin activates its receptor in the same cell. "
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Cellular interactions between neighboring axons are essential for global topographic map formation. Here we show that axonal interactions also precisely instruct the location of synapses. Motoneurons form en passant synapses in Caenorhabditis elegans. Although axons from the same neuron class significantly overlap, each neuron innervates a unique and tiled segment of the muscle field by restricting its synapses to a distinct subaxonal domain-a phenomenon we term synaptic tiling. Using DA8 and DA9 motoneurons, we found that the synaptic tiling requires the PlexinA4 homolog, PLX-1, and two transmembrane semaphorins. In the plexin or semaphorin mutants, synaptic domains from both neurons expand and overlap with each other without guidance defects. In a semaphorin-dependent manner, PLX-1 is concentrated at the synapse-free axonal segment, delineating the tiling border. Furthermore, plexin inhibits presynapse formation by suppressing synaptic F-actin through its cytoplasmic GTPase-activating protein (GAP) domain. Hence, contact-dependent, intra-axonal plexin signaling specifies synaptic circuits by inhibiting synapse formation at the subcellular loci.
"Timing and spatial distribution of gene expression in the rabbit support the evidence of a functional significance of the BMP–BLIMP1 connection for PGC lineage segregation in general, but single BLIMP1-positive cells surrounded by complete ring of BLIMP1-negative ones at stages 2 and 3 (cf. Fig. 5) suggest that the initial step for the successful segregation of PGCs may be a lateral inhibition event in single cells similar to neuroblast generation in Drosophila as the result of the Notch–Delta signaling pathway (Axelrod 2010). Complexity is added to the process as it occurs almost simultaneously with the singling out of presumptive mesoderm cells within the epiblast layer in the same location, the posterior gastrula extension (PGE) area: 10 to 15 single epiblast cells of the PGE express the mesodermal master control gene brachyury at stage 2 (Viebahn et al. 2002), i.e., at a time when the first few BLIMP1-positive epiblast cells appear at the posterior periphery of the PGE area; at stage 3, a handful of BLIMP1-positive cells occupy the very same region as the strong brachyury expression domain overlying the posterior half of the emerging primitive streak (cf. "
[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 · 2.44 Impact Factor
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