Evolution of Genetic Networks Underlying the Emergence of Thymopoiesis in Vertebrates

Abstract

About 500 million years ago, a new type of adaptive immune defense emerged in basal jawed vertebrates, accompanied by morphological innovations, including the thymus. Did these evolutionary novelties arise de novo or from elaboration of ancient genetic networks? We reconstructed the genetic changes underlying thymopoiesis by comparative genome and expression analyses in chordates and basal vertebrates. The derived models of genetic networks were experimentally verified in bony fishes. Ancestral networks defining circumscribed regions of the pharyngeal epithelium of jawless vertebrates expanded in cartilaginous fishes to incorporate novel genes, notably those encoding chemokines. Correspondingly, novel networks evolved in lymphocytes of jawed vertebrates to control the expression of additional chemokine receptors. These complementary changes enabled unprecedented Delta/Notch signaling between pharyngeal epithelium and lymphoid cells that was exploited for specification to the T cell lineage. Our results provide a framework elucidating the evolution of key features of the adaptive immune system in jawed vertebrates.

Genetic Evidence for an Evolutionarily Conserved Role of IL-7 Signaling in T Cell Development of Zebrafish

“…1B). To examine the phenotypes further, we have used an ikaros:gfp transgene; the fluorescent protein is expressed in hematopoietic progenitors cells, including thymocyte precursors, and can thus be used to visualize embryonic hematopoiesis and thymus colonization in real-time (29). High-resolution time-lapse analysis confirmed the results obtained with rag1-specific RNA in situ hybridization.…”

“…3B), properly assembled tcrb genes are expressed and detectable by RT-PCR. The expression of foxn1, a characteristic marker for thymic epithelial cells (29,35), is unaffected, although foxn1-positive cells are less dispersed in the thymic rudiment as a result of the reduced number of hematopietic cells (Fig. 3C).…”

“…The ikaros eGFP line was described previously (29). Briefly, in the original round of mutant identification, 20-30 larvae of each F3 clutch were screened via rag1 in situ hybridization at 120 h postfertilization to detect alterations in thymus development.…”

“…Morphants were generated by injection of anti-sense oligonucleotides (Gene Tools, Philomath, OR) encompassing the sequences of the initiation codons (Table I) at 100 mM as described previously (29).…”

L’épithélium thymique, un passé dans la dualité et un présent unifié

“…Le gène Foxn1 s'est formé par duplication d'un gène ancestral Foxn4 présent chez le poisson, mais pas chez la souris [9]. Une étude de Swann et al [2] montre que l'introduction de FoxN1 chez la souris nude (porteuse d'une mutation spontanée du gène Foxn1) permet de restaurer le développement T, alors que celle de FoxN4 aboutit au développement de cellules B dans le thymus.…”