Available online at www.sciencedirect.com ScienceDirect Notch signalling: sensor and instructor of the microenvironment to coordinate cell fate and organ morphogenesis 1,2 3 1,2 Bethan Lloyd-Lewis , Philippos Mourikis and Silvia Fre During development, stem cells give rise to specialised cell Notch signalling is triggered by interactions between types in a tightly regulated, spatiotemporal manner to drive the Notch receptors and their ligands on adjacent cells formation of complex three-dimensional tissues. While (Box 1). Receptor activation results in Notch target gene mechanistic insights into the gene regulatory pathways that induction, including genes of the Hairy-Enhancer of Split guide cell fate choices are emerging, how morphogenetic (HES) family, which act as repressors of lineage-specific changes are coordinated with cell fate specification remains a determinants. In turn, this juxtacrine signalling mecha- fundamental question in organogenesis and adult tissue nism dynamically regulates lineage specification accord- homeostasis. The requirement of cell contacts for Notch ing to the position of a cell and the composition of its signalling makes it a central pathway capable of linking neighbours. Its simplicity in design — a direct route from dynamic cellular rearrangements during tissue morphogenesis the membrane to the nucleus lacking second messenger with stem cell function. Here, we highlight recent studies that amplification and regulation — belies exceptional com- support a critical role for the Notch pathway in translating plexity, as Notch activation guides cells towards opposing microenvironmental cues into cell fate decisions, guiding the developmental paths in a tissue and time-dependent development of diverse organ systems. manner. Integration with coincident signalling events and mechanical cues also shape Notch pathway activity, Addresses generating the diverse biological outcomes required for 1 Institut Curie, PSL Research University, Inserm, CNRS, Paris, France 2 each context [2]. Notch signalling, therefore, provides an Sorbonne University, UPMC University of Paris VI, Paris, France 3 ideal paradigm to examine how cells combine multiple Universite´ Paris Est Cre´ teil, IMRB U955-E10, Inserm, CNRS, Cre´ teil, France inputs from neighbouring cells and the physical extracel- lular environment to coordinate cell fate specification Corresponding author: Fre, Silvia ([email protected]) with tissue morphogenesis. Current Opinion in Cell Biology 2019, 61:16–23 Notch signalling: bridging spatiotemporal This review comes from a themed issue on Differentiation and control of stem cell specification with organ disease morphogenesis Edited by Sara A Wickstro¨ m and Yingzi Yang The role of Notch in determining cell fate during For a complete overview see the Issue and the Editorial development is well-recognised, and has been exten- Available online 16th July 2019 sively reviewed elsewhere [2–4]. While Notch promotes https://doi.org/10.1016/j.ceb.2019.06.003 cellular differentiation in some contexts (e.g. in skin keratinocytes [5] and in the lung [6]), signal activation 0955-0674/ã 2019 Elsevier Ltd. All rights reserved. is often associated with stem cell maintenance and proliferation, including in muscular, intestinal, hemato- poietic and neural stem cells [7–12]. Indeed, the devel- opmental outcome of Notch signals depends on their integration with a multiplicity of regulatory factors that vary across morphogenetic systems [2]. Cell shape [13], Introduction cellular movements, proximity to local cues (e.g. base- The construction of precise cellular ensembles during ment membrane (BM) attachment) [14] and mechanical tissue development relies on an intricate interplay stimuli associated with local tissue deformations [15] can between cell proliferation, differentiation, communica- all contribute to cell fate determination [16,17]. Thus, tion, migration and death. Among the signalling cues that dynamic changes in cellular composition and tissue coordinate these cellular programs, the Notch pathway is architecture during organ growth and repair expose stem widely recognised as a major determinant of cell fate cells to evolving niche environments, instructing gene across all metazoans. First discovered in Drosophila mel- regulatory networks such as Notch to guide lineage anogaster a century ago, the Notch receptor is a central decisions in a highly regulated, spatiotemporal manner. element of an evolutionarily conserved pathway that Below, we outline designs of Notch signal modulations controls a broad spectrum of cell fate decisions through between stem cells and their surrounding cellular and local cell communication [1]. non-cellular microenvironment, and highlight recent Current Opinion in Cell Biology 2019, 61:16–23 www.sciencedirect.com Notch signalling in stem cell fate and organ morphogenesis Lloyd-Lewis, Mourikis and Fre 17 Box 1 Notch signalling in brief embryonic mammary cells exposed to the BM, while others face the forming lumen; an intriguing hypothesis The central element of the pathway is the plasma membrane protein Notch, which acts both as a receptor and a transcription factor. that warrants further investigation. Notch is initially cleaved in the trans-Golgi network and is presented on the cell surface in a heterodimeric form, tethered together via non- Similarly, coordinated morphogenesis and Notch-mediated covalent interactions. In mammals, the Notch receptor has four lineage diversification was recently described in the devel- paralogues, Notch 1 to Notch 4. Molecularly, the extracellular oping pancreas [23,24 ]. Indeed, excessive endocrine differ- domain of either of the transmembrane ligands, Delta-like-1, Delta- like-2 and Delta-like-4, and Jagged-1 and Jagged-2 (Delta and entiation in Hes1 mutant embryos resulted in ectopic pan- Serrate in Drosophila) on the surface of one cell, interacts with the creas formation [24 ]. This study supports a model where the extracellular domain of the Notch receptor on an adjacent cell. A extension of the dorsal pancreatic bud perpendicularly into series of post-translational modifications modulate the affinity and the associated mesenchyme is ensured by the repressive activity of the Notch receptor and its ligands (reviewed in Ref. [48]). Ligand binding triggers two proteolytic cleavages by ADAM and action of Hes1 on the endocrine determinant Neurogenin3 g-secretase (juxtamembrane and intracellular, respectively) that (Neurog3). A second report also examined the coordina- result in the release of the Notch intracellular domain (NICD) from its tion between pancreas plexus morphogenesis and endo- plasma membrane tether. NICD is subsequently translocated into the crine fate allocation [23]. In this case, morphogenetic nucleus where it forms a complex with the DNA-binding factor RBPJ cues within the epithelial plexus niche, where pancreatic and the co-activator Mastermind-Like (Su(H) and Mastermind in Drosophila). This nuclear complex induces the expression of Notch progenitors reside, initiated endocrine commitment. target genes, among which the most conserved belong to the HES The integration between Neurog3-driven endocrine dif- gene family [49,50]. HES proteins are basic Helix-Loop-Helix (bHLH) ferentiation, Notch-stimulated pancreatic progenitor DNA-binding transcription factors that suppress expression of line- maintenance and epithelial remodelling ensures the age-specifying bHLH genes, such as Mash-1 and Math-1 (neuro- genesis, endocrine lineages), Myogenin (myogenesis) and E2A (B correct balance between cell differentiation and organ lymphopoiesis), controlling cell differentiation in diverse organs, morphogenesis. Precisely how transcription-factor deter- including the nervous system, heart, skeletal muscle, pancreas, minants feedback and are coordinated with pancreatic endodermal endocrine organs and hematocytes [51]. morphogenetic programs remains to be elucidated, although it is likely influenced by concomitant biochem- ical and biomechanical cues (discussed below). studies that describe how spatial arrangements of cells Distinct temporal and spatial patterns of cell differentia- underpin cell fate decisions during tissue morphogenesis tion are also evident during the development of other (Figure 1). tissues. For example, precise regionalisation of ligand expression in thymic epithelial cells was recently shown Notch signalling responds to dynamic reorganisation of to be necessary for establishing discrete Notch niches that the cellular niche instruct T cell specification in the developing thymus The source and availability of Notch ligands are essential [25]. Notch-mediated binary cell fate decisions are also for defining how Notch determines cell fate. In the required for mammalian nephrogenesis, where the nec- context of directional Notch signalling, cellular rearran- essary cell-to-cell interactions are established through a gements can position a given cell in proximity to a Notch morphogenetic process that maintains nephron progeni- ligand-expressing cell that, in turn, determines its tors in aggregates during tubule formation [26,27]. The neighbour’s destiny. In the developing mammary gland, requirement for positional cues to generate diverse and for example, Notch signalling is well-established to be a specialised cell types during organ morphogenesis is critical determinant of luminal cell differentiation evolutionarily conserved, as similar signal regionalisation [18,19 ], one of the two epithelial lineages that constitute is necessary