To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis

Notch signaling forms an evolutionarily conserved juxtacrine pathway crucial for cellular development. Initially identified in Drosophila wing morphogenesis, Notch signaling has since been demonstrated to play pivotal roles in governing mammalian cellular development in a large variety of cell types. Indeed, abolishing Notch constituents in mouse models result in embryonic lethality, demonstrating that Notch signaling is critical for development and differentiation. In this review, we focus on the crucial role of Notch signaling in governing embryogenesis and differentiation of multiple progenitor cell types. Using hematopoiesis as a diverse cellular model, we highlight the role of Notch in regulating the cell fate of common lymphoid progenitors. Additionally, the influence of Notch through microenvironment interplay with lymphoid cells and how dysregulation influences disease processes is explored. Furthermore, bi-directional and lateral Notch signaling between ligand expressing source cells and target cells are investigated, indicating potentially novel therapeutic options for treatment of Notch-mediated diseases. Finally, we discuss the role of cis‑inhibition in regulating Notch signaling in mammalian development.

The feedback regulator Nord controls Dpp/BMP signaling via extracellular interaction with Dally in the Drosophila wing

The Drosophila BMP 2/4 homologue Decapentaplegic (Dpp) acts as a morphogen to regulate diverse developmental processes, including wing morphogenesis. Transcriptional feedback regulation of this pathway ensures tightly controlled signaling outputs to generate the precise pattern of the adult wing. Nevertheless, few direct Dpp target genes have been explored and our understanding of feedback regulation remains incomplete. Here, we employ transcriptional profiling following dpp conditional knockout to identify nord, a novel Dpp/BMP feedback regulator. Nord mutants generated by CRISPR/Cas9 mutagenesis produce a smaller wing and display low penetrance venation defects. At the molecular level, nord encodes a heparin-binding protein and we show that its overexpression is sufficient to antagonize Dpp/BMP signaling. Further, we demonstrate that Nord physically and genetically interacts with the Dpp/BMP co-receptor Dally. In sum we propose that Nord acts with Dally to fine tune Dpp/BMP signaling, with implications for both developmental and disease models.Impact statementFunctional analyses of the Drosophila homologue of Neuron Derived Neurotrophic Factor reveal a new mode of extracellular heparan sulfate proteoglycan regulation required for proper morphogen action.

mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing

Eukaryotic 5’−3’ mRNA decay plays important roles during development and in response to stress, regulating gene expression post-transcriptionally. In Caenorhabditis elegans, deficiency of DCAP-1/DCP1, the essential co-factor of the major cytoplasmic mRNA decapping enzyme, impacts normal development, stress survival and ageing. Here, we show that overexpression of dcap-1 in neurons of worms is sufficient to increase lifespan through the function of the insulin/IGF-like signaling and its effector DAF-16/FOXO transcription factor. Neuronal DCAP-1 affects basal levels of INS-7, an ageing-related insulin-like peptide, which acts in the intestine to determine lifespan. Short-lived dcap-1 mutants exhibit a neurosecretion-dependent upregulation of intestinal ins-7 transcription, and diminished nuclear localization of DAF-16/FOXO. Moreover, neuronal overexpression of DCP1 in Drosophila melanogaster confers longevity in adults, while neuronal DCP1 deficiency shortens lifespan and affects wing morphogenesis, cell non-autonomously. Our genetic analysis in two model-organisms suggests a critical and conserved function of DCAP-1/DCP1 in developmental events and lifespan modulation.

Dynamic 3D tissue architecture directs BMP morphogen signaling during Drosophila wing morphogenesis

SummaryAt the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how Decapentaplegic (Dpp) / Bone Morphogenetic Protein (BMP) signaling and 3D wing morphogenesis are coupled. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia directs the spatial distribution of BMP signaling, revealing how 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.