Thymus organogenesis

2.1. Third Pharyngeal Pouch and Arch Epithelium and Neural Crest-Derived Mesenchyme

Steps of thymus organogenesis and some of the known genes involved in this process are outlined in Fig. 1. The thymus originates from the third pharyngeal pouch and the third and fourth pharyngeal arches. On embryonic d 10, at this location, endodermal epithelium is situated next to neural crest-derived mesenchymal cells. Several studies have shown that mesenchyme plays a critical role for thymus organogenesis and function (39-42). Mesenchymal-epithelial interactions are essential for thymus morphogenesis (e.g., capsule formation, lobulation). The role of the mesenchyme can be substituted in vitro by epidermal growth factor (EGF) or transforming growth factor-a (TGF-a) (40). Pax3 plays a role in the migration of neural crest-derived mesenchyme toward the thymus (43).

Following positioning of the thymus anlage, endodermal epithelium buds and grows to form a more circular structure. According to classical models of thymus organogenesis, rapid circumferential growth of ectodermal epithelium, derived from the ectodermal cervical vesicle, occurs close to the endodermal pouch at this stage. These ectodermal cells supposedly surround the endodermal tissue with a later annotation of the endodermal part to form the inner, medullary, epithelium, and the ectodermal cells to build the outer, cortical, epithelium. Current models of thymus organogenesis have abandoned an involvement of ectoderm (e.g., see refs. 35 and 44).

Patterning and further differentiation of the thymus take place beginning on d 13 of embryonic development, and these steps involve lobulation, segmentation, and formation of medulla-cortex architecture. Medulla-cortex architecture may be influenced by colonization of pro-T cells, a process termed "cross-talk" between thymic epithelium and thymocytes (18,45,46). The term "cross-talk" is more commonly used for mutual interactions of intracellular signaling pathways, and has remained an ill-defined phenomenon pointing vaguely at thymocyte-stroma interactions.

Fig. 1. Thymus organogenesis. (A) Stages of thymus development are depicted schematically closely based on the model proposed by Manley (35). (B) Genes likely to play a role in thymus organogenesis are shown without close timing to the stages shown in A. (C) The exact role of thymus epithelial stem/progenitor cells in thymus organogenesis is not known, but such cells can definitively contribute to medulla-cortex organization and thus to patterning.

outgrowth

Stem cell involvement ?

patterning & differentiation

{morphogenesis) --> medulla cortc\ organization

u - mese nchy in-de pendent

- substituted by EGF or TGF-a & mat ri gel com act-de pendent & con tac t-independent signals are required

Stem cell involvement ?

2.2. Genes Involved in Thymus Organogenesis

Mutations impinging on pharyngeal arch and pouch development abrogate or perturb thymus development. For instance, third pouch development is abrogated in Tbxl-deficient mice (15,16), and null mutations in the eyes absent gene 1 (Eyal) result in morphogenetic defects in thymus, parathyroid, and thyroid development (47). Neural crest migration is controlled by Pax3.

Transcription factors of the hox family are key molecules in the direction of the development of pharyngeal arch-derived organs (i.e., thymus, parathyroid gland, ultimobranchial body). A key gene is Hoxa3 (48), which is expressed in endodermal cells in the third pouch. Hoxa3 appears to be positioned "upstream" of Paxl (49-51) and Pax9 (44,52), both of which are also critical for thymus development, ventral migration of the two lobes, or thy-mocyte development.

The transcription factor Foxnl (12) is essential for the development of the thymic epithelium at the stage of the thymus anlage past the initial induction and outgrowth. Foxn1, allelic with the nude gene, continues to be expressed in both cortical and medullary epithelium during adult life (13), but the functional significance of this expression is not known. The block in thymus development in nude mice places the Foxn1 gene between Hoxa3 and Pax9 (44). Bleul and Boehm identified several target genes of Foxn1 (53), and have proposed that misguided chemokine expression may contribute to the lack of pro-T cell homing to the nude thymus (54). An identification of those target genes of the Foxn1 gene that direct thymus development may be the key to deepen the understanding of thymus epithelial differentiation. For a detailed discussion of other genes involved in thymus organogenesis, see the review by Manley (35).

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