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From Nematode Neurons to Vertebrate Neural Crest

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From Nematode Neurons to Vertebrate Neural Crest Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION types in vertebrate embryos, and thus a potential model Evolutionary conservation for understanding the molecular basis of migratory pro- of cell migration genes: cesses. However, due to the difficulty of visualizing mo- tile cells in living vertebrate embryos, the problem of from nematode neurons neural crest migration has not been particularly ame- to vertebrate neural crest nable to genetic dissection, and only a limited number of genes that affect aspects of neural crest migration have Yun Kee,1,3 Byung Joon Hwang,1,2,3 been identified (Halloran and Berndt 2003). 1,2 The feasibility of genetic screens in invertebrates, Paul W. Sternberg, such as Caenorhabditis elegans and Drosophila melano- 1,4 and Marianne Bronner-Fraser gaster, has allowed the isolation of mutants that disrupt various aspects of cell migration (Garriga and Stern 1994; 1Division of Biology, California Institute of Technology, Montell 1999). For example, C. elegans hermaphrodite- Pasadena, California 91125, USA; 2Howard Hughes Medical specific neurons (HSN) undergo long-range migrations Institute, California Institute of Technology, Pasadena, from their location at birth in the tail to positions flank- California 91125, USA ing the gonadal primordium in the midbody of the ani- Because migratory cells in all animals share common mal (Fig. 1B). Forward genetic screening has identified 15 genes required for HSN migration, including transcrip- properties, we hypothesized that genetic networks in- tion factors, signaling, and adhesion molecules (Garriga volved in cell migration may be conserved between and Stern 1994). nematodes and vertebrates. To explore this, we per- In the present study, we take a comparative genomic formed comparative genomic analysis to identify verte- analysis, which combines the information of inverte- brate orthologs of genes required for hermaphrodite- brate genetics and complete genome sequences from ani- specific neuron (HSN) migration in Caenoryhabditis mal models. We address the question of whether the ge- elegans, and then examined their expression and func- netic networks involved in long-range cell migrations tion in the vertebrate neural crest. The results demon- are conserved across the large evolutionary distance be- strate high conservation of regulatory components in- tween C. elegans HSN neurons and vertebrate neural volved in long-range migrations across diverse species. crest cells. Our study demonstrates that the neural crest, a uniquely vertebrate cell type, shares common regula- Although the neural crest is a vertebrate innovation, the tory elements for cell migration programs utilized in the results suggest that its migratory properties evolved by nematode, suggesting that the role of these genes was utilizing programs already present in the common ver- present in the common ancestor of vertebrates and in- tebrate–invertebrate ancestor. vertebrates. We offer this comparative genomic analysis Supplemental material is available at http://www.genesdev.org as a powerful tool for identifying regulatory genes, in- cluding transcription factors, governing vertebrate-spe- Received November 7, 2006; revised version accepted January cific processes. 9, 2007. Results and Discussion During animal development, selected cell populations Genomic screening of vertebrate orthologs of HSN undergo complex and stereotypic migrations that are migration genes critical for proper pattern formation of the embryo. Cell migration is important for both embryonic and adult tis- Given that morphological and biochemical aspects of sues, since its abnormal regulation causes developmen- cell migratory behavior appear to be largely conserved tal defects and can result in metastasis. However, the across species, we posited that the genetic mechanisms molecular mechanisms controlling cell migration re- controlling long-range cell migration may also be con- main poorly understood, particularly in vertebrates. served between evolutionarily distant animals. To test The neural crest is a stem cell-like multipotent cell this idea, we asked whether genes involved in the mi- population unique to vertebrates. Neural crest progeni- gration of C. elegans HSN neurons were also utilized for tors migrate from their site of origin in the central a similar purpose in the neural crest, thus offering a nervous system to numerous tissues in the periphery bioinformatics approach for identifying candidate cell (Fig. 1A); for example, cranial neural crest cells leave the migration genes in vertebrates. To this end, we picked 15 neural tube and migrate in defined streams to surround genes that are essential for HSN migration and identified the eye, the frontonasal process, and the branchial their putative vertebrate orthologs. We have tentatively arches. They subsequently differentiate into neurons, defined the vertebrate ortholog as the gene having the glia, pigment cells, and much of the craniofacial skeleton highest identity score in the tBLAST analysis against all (Knecht and Bronner-Fraser 2002; Crane and Trainor available vertebrate genome sequences. We then used 2006). The neural crest is one of the most motile of cell the putative vertebrate orthologs to identify chicken or Xenopus laevis genes and their available EST sequences [Keywords: Neural crest; cell migration; C. elegans HSN; comparative (Table 1; Supplementary Table S1). genomic analysis] These 15 genes included six transcription factors, (egl- 3 These authors contributed equally to this work. 5, egl-18, egl-27, egl-43, ham-1, and ham-2) (Chisholm 4Corresponding author. E-MAIL [email protected]; FAX (626) 395-7717. 1991; Garriga et al. 1993; Garriga and Stern 1994; Guen- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1509307. ther and Garriga 1996; Baum et al. 1999; Herman et al. GENES & DEVELOPMENT 21:391–396 © 2007 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/07; www.genesdev.org 391 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Kee et al. groups), to which the C. elegans gene belongs (Tatusov et al. 2003). We further analyzed these six genes by OrthoMCL, a method that constructs ortholog groups using a Markov Cluster algorithm (Li et al. 2003). This program assigned mig-2 to an ortholog group OG1_290 together with other C. elegans paralogs and RAC1 of other species, suggesting that mig-2 may be one of the “recent” paralogs or co-orthologs, which are equally re- lated to orthologs in other species. The ortholog groups for egl-5 (OG1_29675), egl-18 (OG1_64731), ham-2 (OG1_39625), and mig-1 (OG1_39065) contained only nematode genes, and the one for unc-71 (OG1_17783) contained yeast, nematode, and fly genes, suggesting Figure 1. Schematic diagram of long-range cell migration of verte- that they are related as “ancient” paralogs, perhaps ac- brate neural crest and C.elegans hermaphrodite-specific neurons. counting for why the reciprocal BLAST from their cor- (A) Cranial neural crest cells emigrate from the neural tube and responding putative vertebrate orthologs identified their migrate to different sites in the periphery of the embryo (stage 9 paralogs as best matches in C. elegans genome. chick embryo). The diagram on the right shows a transverse section through the midbrain level with neural crest cells emigrating out of dorsal neural tube and migrating into the head mesenchyme. (MB) Midbrain. (B) HSN neurons migrate from the tail to gonadal primo- Expression of HSN migration genes in neural crest dium in the C. elegans embryo. We first examined the expression patterns of these tran- scripts in chicken embryos, focusing on initial stages of 1999), three signaling ligands or receptors (egl-20, ina-1, neural crest migration in the head. The EST sequences or and mig-1) (Harris et al. 1996; Baum and Garriga 1997; partial sequences obtained by PCR, based on genomic Maloof et al. 1999), one extracellular matrix molecule sequences, were used to prepare RNA probes for subse- (epi-1) (Forrester and Garriga 1997), four intracellular sig- quent in situ hybridization. Gene expression in neural naling molecules (mig-2, mig-10, unc-34, and unc-73) crest cells was examined as previously described (Kee (Forrester and Garriga 1997; Manser et al. 1997; Zipkin et and Bronner-Fraser 2001, 2005). At early stages of ner- al. 1997; Steven et al. 1998), and one protease (unc-71) vous system formation, most of the chicken orthologs (Huang et al. 2003). We obtained all 15 chicken orthologs were expressed in premigratory and migrating neural from the complete chick genome sequence and five X. crest cells in the midbrain as shown in whole-mount and laevis orthologs from available partial genome sequence sections of in situ hybridized embryos (Fig. 2A). The and EST databases (Table 1; Supplementary Table S1). chicken orthologs of egl-20, egl-27, epi-1, ham-1, ham-2, Reciprocal BLAST analysis to the C. elegans genome mig-2, mig-10, unc-34, and unc-73 were expressed in pre- matched nine vertebrate orthologs as having the highest migratory neural crest cells in the dorsal neural tube. identity scores to their corresponding C. elegans genes Sections through these embryos revealed that most (Supplementary Table S1); the other six putative or- genes were also expressed on newly emigrated neural thologs were matched to their corresponding best crest cells on the dorsal neural tube as they embark on match by virtue
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