New genes in the evolution of the neural crest differentiation program

Abstract

Background: Development of the vertebrate head depends on the multipotency and migratory behavior of neural crest derivatives. This cell population is considered a vertebrate innovation and, accordingly, chordate ancestors lacked neural crest counterparts. The identification of neural crest specification genes expressed in the neural plate of basal chordates, in addition to the discovery of pigmented migratory cells in ascidians, has challenged this hypothesis. These new findings revive the debate on what is new and what is ancient in the genetic program that controls neural crest formation.

Results: To determine the origin of neural crest genes, we analyzed Phenotype Ontology annotations to select genes that control the development of this tissue. Using a sequential blast pipeline, we phylogenetically classified these genes, as well as those associated with other tissues, in order to define tissue-specific profiles of gene emergence. Of neural crest genes, 9% are vertebrate innovations. Our comparative analyses show that, among different tissues, the neural crest exhibits a particularly high rate of gene emergence during vertebrate evolution. A remarkable proportion of the new neural crest genes encode soluble ligands that control neural crest precursor specification into each cell lineage, including pigmented, neural, glial, and skeletal derivatives.

Conclusion: We propose that the evolution of the neural crest is linked not only to the recruitment of ancestral regulatory genes but also to the emergence of signaling peptides that control the increasingly complex lineage diversification of this plastic cell population.

Figure 1

Gene phylogeny was explored using a sequential blast pipeline. (a) All known mouse proteins were sequentially blasted (cutoff value E = 10^-4) against available databases and then classified according to their appearance into seven different categories: prokaryota (pro), eukaryota (euk), metazoa (met), deuterostomia (deu), chordata (cor), vertebrata (ver), and mammalia (mam). (b) The table shows the number of mouse genes assigned to each category compared with their estimated age in millions of years. (c) Graphical representation of the global gene phylogeny.

Figure 2

Tissue-specific profiles of gene emergence. The accumulative number of emerging genes (y-axis) in the deuterostomia-mammalia evolutionary window (x-axis) is represented for different tissue-specific genetic programs. We termed these representations gene emergence plots. At the chordate-vertebrate transition the rate of gene emergence (ger) was estimated for the different genetic programs. (a) Using mouse phenotypic annotations we calculated ger values between chordata and vertebrata for each main phenotype structure in the database. Structures are highlighted from blue to yellow, according to decreasing values of ger. Neural crest derivative structures are present within the highest ger values (red box). (b) Plots of representative structures of each class of ger value: class I = ger > 3; class II = 3 > ger > 1.5; and class III: ger < 1.5.

Figure 3

Gene emergence plots of neural crest derivatives. Graphs and gene emergence rate (ger) values associated both with (a) the total collection of neural crest genes and (b) the different bone, nervous system, and pigmentation derivatives.

Figure 4

Emerging ligands control the specification of neural crest precursors. The progressive determination of neural crest (NC) precursors into different cell lineages is represented in the scheme with a code of colors. Superimposed on this, the collection of new growth factors appearing first in vertebrates is depicted. The role of each ligand in controlling the specification/survival of each particular neural crest derivative is indicated with a corresponding code of colors. alpha-MSH, alpha-melanocyte-stimulating hormone; End, endothelin; GDNF, glial-derived neurotropic factor; NT, neurotropin; Nppc, natriuretic peptide precursor.