Thymus Development

Evolutionary onset of thymus development coincides with that of the jaw. It has been speculated that with the appearance of the jaw dietary changes as well as increased injuries and infections occurred, creating selective pressure for the development of an organ of high output of immune cells with a diverse and anticipatory repertoire. Thus the cartilaginous (chondrichthyes) and bony fishes (osteichthyes) are the first vertebrates in which a thymus can be identified.
The thymus is the centerpiece of the adaptive immune system because it provides the environment for generation and selection of large numbers of antigen-specific T cells.

The thymus is also the organ where autoimmunity is controlled either by deleting or anergizing autoreactive T cells (“central tolerance”). Similarly to humans, zebrafish thymus development depends on contribution from all three germlayers (see Fig.1). The hindbrain rhombomeres (Fig.1, left panel) from which neural crest cells arise are stained with Krox-20 (third and fifth rhombomere, r3 and r5). Neural crest cell (NCC) expression of forkhead 6 (Fkd6) in 15-somite (a developmental stage, approximately 20 hpf, at which 15 body segments can be counted) wild-type embryo is shown in the middle panel. Arrow indicates the third, postotic (behind the ear vesicle) stream of neural crest that invades the third and fourth pharyngeal pouches. In d2 wild-type embryos Hoxa-3 is expressed in rhombomeres 5 and 6 (arrow) and pharyngeal endoderm (arrowhead). Expression of Nkx2.3 is seen in pharyngeal pouches (middle top panel, arrow) and in anterior gut (asterisk) in d2 wild-type larva. Mesodermally derived hematopoietic progenitor cells, stained with c-myb (right top panel, arrow), presumably arise from the dorsal aorta in zebrafish embryos at 36 hpf. Pro-T cells probably originate from this area and invade the thymic rudiment. Alcion blue staining of skeletal elements of the head region in a d7 wild-type zebrafish shows arches p1 to p7 (left middle panel). Asterisk indicates the third pharyngeal pouch, where thymus originates. Thymus (right middle panel, grey arrow) of d7 wild-type zebrafish with heterogeneous cell populations, consisting of lymphoblasts and thymic epithelial cell. Expression of Rag-1 in d8 wild-type embryo is seen in the olfactory pit (bottom panel, grey horizontal arrows) and bilateral thymi (arrows).

In adults, the thymus consists of a cortical and medullary compartment (see Fig.2), as identified by differential expression of Rag-1 and TCR alpha. Similarly to mammals, thymus involution coincides with sexual maturation. In the past we have created a number of mutants of thymus development, and positional cloning of the affected genes in underway.