Junqueira Alves C et al. (2019), Origin and evolution of plexins, semaphorins, a...

ECB-ART-49938

Sci Rep 2019 Feb 13;91:1970. doi: 10.1038/s41598-019-38512-y.

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Origin and evolution of plexins, semaphorins, and Met receptor tyrosine kinases.

Junqueira Alves C , Yotoko K , Zou H , Friedel RH .

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The transition from unicellular to multicellular organisms poses the question as to when genes that regulate cell-cell interactions emerged during evolution. The receptor and ligand pairing of plexins and semaphorins regulates cellular interactions in a wide range of developmental and physiological contexts. We surveyed here genomes of unicellular eukaryotes and of non-bilaterian and bilaterian Metazoa and performed phylogenetic analyses to gain insight into the evolution of plexin and semaphorin families. Remarkably, we detected plexins and semaphorins in unicellular choanoflagellates, indicating their evolutionary origin in a common ancestor of Choanoflagellida and Metazoa. The plexin domain structure is conserved throughout all clades; in contrast, semaphorins are structurally diverse. Choanoflagellate semaphorins are transmembrane proteins with multiple fibronectin type III domains following the N-terminal Sema domain (termed Sema-FN). Other previously not yet described semaphorin classes include semaphorins of Ctenophora with tandem immunoglobulin domains (Sema-IG) and secreted semaphorins of Echinoderamata (Sema-SP, Sema-SI). Our study also identified Met receptor tyrosine kinases (RTKs), which carry a truncated plexin extracellular domain, in several bilaterian clades, indicating evolutionary origin in a common ancestor of Bilateria. In addition, a novel type of Met-like RTK with a complete plexin extracellular domain was detected in Lophotrochozoa and Echinodermata (termed Met-LP RTK). Our findings are consistent with an ancient function of plexins and semaphorins in regulating cytoskeletal dynamics and cell adhesion that predates their role as axon guidance molecules.

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	Figure 1. Plexins and semaphorins of choanoflagellates and non-bilaterian Metazoa. (A) The genomes of choanoflagellates M. brevicollis and S. rosetta each contain one plexin (Plexin-1) and one semaphorin with fibronectin type III (FNIII) and SEA domains (Sema-FN1). (B) The sponge A. queenslandica has six plexins, four of which with truncated intracellular domain. The four transmembrane semaphorins have a Sema plus PSI architecture (Sema1A-1C) or carry in addition fibronectin type III domains (Sema-FN1). (C) The comb jelly M. leidyi has four plexins, and two classes of semaphorins: Sema1A-1C are secreted semaphorins with a Sema plus PSI architecture, Sema-IG1 to -IG6 are transmembrane semaphorins with two Ig domains in tandem arrangement. (D) The placozoan T. adhaerens has two plexins, Plexin-A1 and -A2, and two transmembrane semaphorins: Sema-FN1 with a single FNIII domain, and Sema5A with the typical architecture of class 5 semaphorins containing multiple thrombospondin 1 (TSP1) domains. (E) The cnidarian N. vectensis has one Plexin-1 and one Sema5A with multiple TSP1 domains. Protein domains: PSI, domain found in plexins, semaphorins, integrins; IPT, immunoglobulin-like fold shared by plexins and transcription factors; Ras-GAP, Ras GTPase activating protein; Ig: immunoglobulin domain. Darker blue for FNIII domains indicates higher annotation certainty. Asterisks indicate missing sequence information. Phylogenetic tree after35; dashed line encircles the clades shown in this figure. Photo credits: M. brevicollis and S. rosetta: Mark Dayel64 (mark@dayel.com; http://www.dayel.com/choanoflagellates; CC BY-SA 3.0; https://creativecommons.org/licenses/by-sa/3.0/legalcode); A. queenslandica: Marcin Adamski; M. leidyi: William Browne; T. adhaerens: Oliver Voigt; N. vectensis: Eric Roettinger.
	Figure 2. Conservation between choanoflagellate and human plexins. Plot of protein sequence conservation between choanoflagellate Plexin-1 (S. rosetta and M. brevicollis) and human Plexin-A1 and Plexin-A4. Overall domain arrangement is conserved, with the highest degree of sequence conservation in the Ras-GAP domain, interrupted by the insert of a lesser conserved RBD domain. The conservation pattern of the Sema domain reflects the seven blade propeller structure. Window size for similarity scoring was set to 50 aa. The y-axis indicates similarity score as calculated by plotcon algorithm (http://emboss.open-bio.org/rel/dev/apps/plotcon.html). See also Figs S1–S3 for alignments and secondary structure prediction.
	Figure 3. Plexins, semaphorins, and Met and Met-LP RTKs of Protostomia. (A,B) The genomes of the annelid C. teleta (A) and the sea hare A. californica (B) each contain two plexins: Plexin-1 and -2, and three semaphorins: Sema1A, 2A, and 5A. One Met and one Met-LP RTK each were also detected. (C) The nematod C. elegans has two plexins and three semaphorins (wormbase.org). (D) The centipede S. maritima has two plexins: Plexin-1 and -2, and five semaphorins: Sema1A-1C, 2A, and 5A. (E) The fruit fly D. melanogaster has two plexins and five semaphorins (flybase.org). Protein domains: see legend of Fig. 1. Asterisks indicate missing sequence. Dashed line in phylogenetic tree encircles clades shown in this figure. Photo credits: C. teleta: François Michonneau (https://francoismichonneau.net/photos/capitella-telata) © 2018 by François Michonneau (CC-BY 4.0); A. californica: Genevieve Anderson; C. elegans: Bob Goldstein; S. maritima: Carlo Brena; D. melanogaster: Hans Smid.
	Figure 4. Plexins, semaphorins, Met, and Met-LP RTKs of Deuterostomia. (A) Expansion of plexins and semaphorins occurred in the genome of the starfish A. planci. Eleven plexins were detected, grouped into two classes (Plexin-A1 to -A3 and Plexin-B1 to -B8), as well and four Met-LP and one Met RTK. Two classes of secreted semaphorins were detected: Sema-SI with a Sema domain, a PSI-like domain, and an Ig domain (Sema-SI1 to -SI4), and Sema-SP with a Sema plus PSI domain. Additionally, the transmembrane semaphorins Sema5A and Sema6A are detected. (B) The lancelet B. belcheri has two plexins, one Met RTK, and three transmembrane semaphorins: Sema5A, 6A, and 6B. (C) Expansion of plexins and semaphorins occurred in the lineage of Vertebrata, as exemplified by the nine plexins, twenty semaphorins, and two Met RTKs in the genome of H. sapiens (genenames.org). Protein domains: see legend of Fig. 1. Asterisks indicate missing sequence. Dashed line in phylogenetic tree encircles the clades shown in this figure. Photo/image credits: A. planci: Denis Zorzin; B. belcheri: Arthur Anker; H. sapiens: NASA.
	Figure 5. Phylogenetic tree of Sema domain containing proteins. Unrooted representation of a phylogenetic hypothesis inferred by a Bayesian method with the aid of the software MrBayes 3.2.6 implemented on CIPRES63 based on alignment of all Sema plus PSI domain sequences of all proteins described in this study. The “1.0” label in the center is the posterior probability at this branch point calculated by MrBayes. Red lines indicate semaphorins, blue lines plexins, green lines Met RTKs, and orange lines Met-LP RTKs. The plexins and semaphorins of choanoflagellates branch off from the base of the respective plexin and semaphorin clades. Human plexin classes (Plexin-A and Plexin-B/C/D) and bilaterian semaphorin classes (Sema1–7) are indicated to provide reference to the detailed tree representations shown in Figs 6 and 7. Scale bar represents peptide sequence divergence of the sequences.
	Figure 6. Phylogenetic tree of plexins and Met and Met-LP RTKs. Detailed phylogenetic hypothesis (complete hypothesis shown in Fig. 5) of plexin, Met, and Met-LP sequences. For clarity, semaphorin sequences are collapsed (triangle). Numbers beside each internal node correspond to posterior probability of the Bayesian phylogenetic inference of each group calculated by MrBayes 3.2.6. Met-LPs and Mets are highlighted by shaded orange and yellow boxes, respectively. The branch lengths are proportional to scale bar and represent the peptide sequence divergence of the sequences included in the tree. Species acronyms: Choanoflagellida (in red): Mbrev, M. brevicollis; Srose, S. rosetta; non-bilaterian Metazoa (in green): Aquee, A. queenslandica; Mleid, M. leidyi; Tadha, T. adhaerens; Nvect, N. vectensis; Protostomia (in purple): Ctele, C. teleta; Acali, A. californica; Celeg, C. elegans; Smari, S. maritima; Dmela, D. melanogaster; Deuterostomia (in blue): Aplan, A. planci; Bbelc, B. belcheri; Hsapi, H. sapiens.
	Figure 7. Phylogenetic tree of semaphorins. Detailed phylogenetic hypothesis (complete hypothesis shown in Fig. 5) of semaphorin sequences. For clarity, plexin, Met, and Met-LP sequences are collapsed (triangle). Numbers next to internal nodes correspond to posterior probability of the Bayesian phylogenetic inference of each group calculated by MrBayes 3.2.6. The orthologous group of class 5 semaphorins is highlighted by shaded green box. The branch lengths are proportional to scale bar and represent peptide sequence divergence of the sequences included in the tree. Species acronyms: Choanoflagellida (in red): Mbrev, M. brevicollis; Srose, S. rosetta; non-bilaterian Metazoa (in green): Aquee, A. queenslandica; Mleid, M. leidyi; Tadha, T. adhaerens; Nvect, N. vectensis; Protostomia (in purple): Ctele, C. teleta; Acali, A. californica; Celeg, C. elegans; Smari, S. maritima; Dmela, D. melanogaster; Deuterostomia (in blue) Aplan, A. planci; Bbelc, B. belcheri; Hsapi, H. sapiens.
	Figure 8. Model of evolutionary origin of plexins and semaphorins. Protein models above taxon names indicate presence of plexin and semaphorin classes in the respective clade (semaphorin class names denoted). Potential origins of semaphorin classes in ancestral lineages are indicated. A plexin and a class FN semaphorin may have been present in a common ancestor of Chonaflagellida and Metazoa. Loss of FN domains may have led to class 1 semaphorins of non-bilaterian Metazoa. The Sema5 class may have originated in a common ancestor of Placozoa, Cnidaria, and Bilateria (note absence in Nematoda). Semaphorins with Ig domains may have evolved twice independently, in Ctenophora as Sema-IG, and in Bilateria as classes Sema2, -SI, 3, 4, and 4. Protein domains: see legends of Figs 1, 3, and 4. Photo/image credits: M. brevicollis and S. rosetta: Mark Dayel64 (mark@dayel.com; http://www.dayel.com/choanoflagellates; CC BY-SA 3.0; https://creativecommons.org/licenses/by-sa/3.0/legalcode); A. queenslandica: Marcin Adamski; M. leidyi: William Browne; T. adhaerens: Oliver Voigt; N. vectensis: Eric Roettinger; C. teleta: François Michonneau (https://francoismichonneau.net/photos/capitella-telata) © 2018 by François Michonneau (CC-BY 4.0); A. californica: Genevieve Anderson; C. elegans: Bob Goldstein; S. maritima: Carlo Brena; D. melanogaster: Hans Smid; A. planci: Denis Zorzin; B. belcheri: Arthur Anker; H. sapiens: NASA.
	Figure 9. Model of evolutionary origin of Met and Met-LP RTKs. Protein models below taxon brackets indicate presence of Met-LPs and/or Mets in the respective clade. Phylogenetic data suggests a scenario in which an ancestral Met RTK might have evolved in a common ancestor of Bilateria. Met-LPs might have formed twice independently by similar tyrosine kinase domain acquisition events in lineages leading to Lophotrochozoa and Echinodermata (indicated by green plus signs). Loss of Met RTKs would have occurred in the lineage leading to Ecdysozoa (indicated by red minus signs). Protein domains: see legends of Figs 1, 3, and 4. Photo/image credits: C. teleta: François Michonneau (https://francoismichonneau.net/photos/capitella-telata) © 2018 by François Michonneau (CC-BY 4.0); A. californica: Genevieve Anderson; C. elegans: Bob Goldstein; S. maritima: Carlo Brena; D. melanogaster: Hans Smid; A. planci: Denis Zorzin; B. belcheri: Arthur Anker; H. sapiens: NASA.

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