Origin and evolution of the Notch signalling pathway: an overview from eukaryotic genomes

Abstract

Background: Of the 20 or so signal transduction pathways that orchestrate cell-cell interactions in metazoans, seven are involved during development. One of these is the Notch signalling pathway which regulates cellular identity, proliferation, differentiation and apoptosis via the developmental processes of lateral inhibition and boundary induction. In light of this essential role played in metazoan development, we surveyed a wide range of eukaryotic genomes to determine the origin and evolution of the components and auxiliary factors that compose and modulate this pathway.

Results: We searched for 22 components of the Notch pathway in 35 different species that represent 8 major clades of eukaryotes, performed phylogenetic analyses and compared the domain compositions of the two fundamental molecules: the receptor Notch and its ligands Delta/Jagged. We confirm that a Notch pathway, with true receptors and ligands is specific to the Metazoa. This study also sheds light on the deep ancestry of a number of genes involved in this pathway, while other members are revealed to have a more recent origin. The origin of several components can be accounted for by the shuffling of pre-existing protein domains, or via lateral gene transfer. In addition, certain domains have appeared de novo more recently, and can be considered metazoan synapomorphies.

Conclusion: The Notch signalling pathway emerged in Metazoa via a diversity of molecular mechanisms, incorporating both novel and ancient protein domains during eukaryote evolution. Thus, a functional Notch signalling pathway was probably present in Urmetazoa.

Figure 1

Major components and auxiliary factors of the Notch signalling pathway as described in Bilateria (modified from [16]). Most of the mentioned components are studied hereafter. S1 to S3 represent the cleavage sites. See Table 1 for complete names and functions of the components.

Figure 2

List of the 35 species selected for the study, representing the 8 major clades of eukaryotes. Colour code: Opistokonta (blue); Amoebozoa (light blue); Plantae (green); Rhizaria (yellow); Alveolata (orange); Heterokonta (pink); Discicristata (violet); Excavata (grey). Data sets and data sources are also indicated. WGS: whole genome available; EST: only EST available. O. carmela: Compagen: ; PEP: . JGI: . NCBI: . TIGR: .

Figure 3

Presence or absence of Notch signalling pathway components and auxiliary factors in eukaryotes. Colour code: In black: genes present. In white: genes absent. In grey: not all diagnostic domains found. In white with an asterisk: incomplete data (EST) do not allow definitive conclusions. In curly bracket: the four members of the γ-secretase complex. Asco = Ascomycota; Basidio = Basidiomycota; CHOANO = Choanoflagellata; DICTYO = Dyctiostellida; PELO = Pelobionta; VIRIDI = Viridiplantae; Embryo = Embryophyta; Volvo = Volvolcaceae; APIC = Apicomplexa; OOMY = Oomycota; BACILLA = Bacillariophyta; EUGLENO = Euglenozoa; Kineto = Kinetoplastida; HETEROLO = heterolobozoa.

Figure 4

Origin of Notch signalling pathway components in Unikonta (modified from [16]). Each colour represents the origin (see figure inset for the colour code) of the gene inferred from our study on the basis of the phylogenetic hypothesis proposed in [45,46].

Figure 5

Bayesian phylogram of Notch representative proteins. Posterior probabilities (greater than 0.50) are indicated next to the node. The Notch families 1, 2 and 3 are presented respectively in yellow, blue and green boxes.

Figure 6

Domain arrangement of Notch proteins in metazoans. Deuterostomes, protostomes and non-bilaterian metazoans are presented in red, blue and green respectively. Phylogenetic hypothesis based on [45,46]. See figure inset for the domain legends.

Figure 7

Bayesian phylogram of DSL representative proteins. Posterior probabilities (greater than 0.50) are indicated next to the node. In blue boxes, most of the Delta sequences split in three clades. In red box, the Jagged representatives.

Figure 8

Domain arrangement of Delta proteins in metazoans. Deuterostomes, protostomes and non-bilaterian metazoans are presented in red, blue and green respectively. Phylogenetic hypothesis based on [45,46]. See figure inset for the domain legends.

Figure 9

Domain arrangement of Jagged proteins in metazoans. Deuterostomes, protostomes and non-bilaterian metazoans are presented in red, blue and green respectively. Phylogenetic hypothesis based on [45,46]. See figure inset for the domain legends.

Figure 10

Scenarios proposed for the emergence of the constitutive domains of DSL ligands and Notch receptors during eukaryote evolution. These scenarios are inferred from our analyses on the basis of the phylogenetic hypotheses of Baldauf 2003 [36] and the application of the principle of parsimony. The left and the right halves of the figure represent the two rooting hypotheses for the eukaryotes. A line represents the appearance of a domain, a cross represents the loss of a domain. Each colour corresponds to a specific domain (see figure inset). Domain presences are summarized under each taxa.

Figure 11

Scenarios proposed for the emergence of the constitutive domains of the receptor regulator Mindbomb during eukaryote evolution. These scenarios are inferred from our analyses on the basis of the phylogenetic hypotheses of Baldauf 2003 [36] and the application of the principle of parsimony. The left and the right halves of the figure represent the two rooting hypotheses for the eukaryotes. A line represents the appearance of a domain, a cross represents the loss of a domain. Each colour corresponds to a specific domain (see figure inset). Domain presences are summarized under each taxa.

Figure 12

Scenarios proposed for the emergence of the constitutive domains of Su(H) and Furin during eukaryote evolution. These scenarios are inferred from our analyses on the basis of the phylogenetic hypotheses of Baldauf 2003 [36] and the application of the principle of parsimony. The left and the right halves of the figure represent the two rooting hypotheses for the eukaryotes. A line represents the appearance of a domain, a cross represents the loss of a domain. Each colour corresponds to a specific domain (see figure inset). Domain presences are summarized under each taxa.

Figure 13

Alternative scenarios concerning the evolution of the DSL ligands (Delta, Serrate and Jagged) in Metazoa, based on the phylogenetic hypothesis of [46]. The EGF+VWC association found in the genome of Trichoplax may be considered either as specific to the placozoan lineage (scenario I) or as an intermediate step involved in the subsequent formation of Jagged/Serrate (scenario II). Domains are represented in different colours as indicated in the figure inset (signal peptide and transmembrane domain are excluded for clarity of presentation). Red and green lines indicate proposed occurrence period of the events.