Mechanisms of thymus organogenesis and morphogenesis - PubMed (original) (raw)

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Mechanisms of thymus organogenesis and morphogenesis

Julie Gordon et al. Development. 2011 Sep.

Abstract

The thymus is the primary organ responsible for generating functional T cells in vertebrates. Although T cell differentiation within the thymus has been an area of intense investigation, the study of thymus organogenesis has made slower progress. The past decade, however, has seen a renewed interest in thymus organogenesis, with the aim of understanding how the thymus develops to form a microenvironment that supports T cell maturation and regeneration. This has prompted modern revisits to classical experiments and has driven additional genetic approaches in mice. These studies are making significant progress in identifying the molecular and cellular mechanisms that control specification, early organogenesis and morphogenesis of the thymus.

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Figures

Fig. 1.

Fig. 1.

Thymus structure. (A) Structure of the thymus. The thymus is an epithelial organ surrounded by a mesenchymal capsule. It can be divided into a central medulla (m) region, which contains medullary thymic epithelial cells (mTECs), and an outer cortex (c), which contains cortical thymic epithelial cells (cTECs). (B) Histology of the thymus. Hematoxylin and eosin-stained sagittal section of an adult mouse thymus, highlighting the thymus subcompartments. (C) T cell development in the thymus. The migratory route of thymocytes through the thymus, and their differentiation steps are shown. The outer mesenchymal capsule is indicated by solid lines, the cortico-medullary junction (CMJ) is indicated by a dashed line. Thymocytes (white) enter the thymus via large blood vessels at the CMJ and commit to the T cell fate. In the cortex, thymocytes differentiate through CD4–CD8– double-negative 1-4 (DN1-4) stages to the CD4+CD8+ double-positive (DP) stage and undergo positive selection (indicated by a gradual change from dark to light purple); these events are mediated by interactions with cortical thymic epithelial cells (cTEC; blue). DP cells then migrate back through the cortex and differentiate into either CD4+ or CD8+ single-positive (SP) T cells. The SP cells then cross the CMJ and enter the medulla, where they interact with multiple medullary TECs (mTECs; green) during negative selection and then leave via the vasculature. Dendritic cells in the medulla (yellow) also participate in the process of negative selection. (D) Immunostaining showing cellular organization in the postnatal thymus. In the left panel, pan-keratin (red) highlights the epithelial network; CD31 (blue) labels endothelial cells; green is collagen IV, which labels perivascular matrix; the dotted lines show the cortico-medullary boundary and the capsular boundary of the cortex. The right panel shows the epithelial network (labeled with keratin-8, purple) in the cortical region. Differential interference contrast imaging allows visualization of thymocytes (arrows) and of epithelial cells `wrapping' around them.

Fig. 2.

Fig. 2.

An overview of thymus development. (A) The pharyngeal pouches (pp) form sequentially on the lateral surfaces of the foregut, with the third pouches (pp3) appearing at E9.5. Gcm2 expression marks the parathyroid domain (blue) from E9.5 onwards. (B) The fourth pouch appears by E10.5. (C) By E11.5, third pouches have developed into primordia that are ready to detach from the pharynx. At this stage, the primordia are patterned into thymus (red) and parathyroid (blue) domains as indicated by Foxn1 and Gcm2 expression, respectively. (D) At E12.5, the primordia have detached from the pharynx, and the parathyroids (blue) have begun to separate from the thymus lobes (red). (E) By E13.5, the parathyroids (blue) have separated from the thymus (red) and remain adjacent to the thyroid (purple). Some parathyroid cells detach from the main organ, and a few remain attached to the thymus. (F) By the newborn stage, the organs are in their final positions, shown here relative to the thyroid and the heart (pink). In panels B and C, note that the pouch and primordium on the embryo's right are slightly advanced relative to the left (see Box 3). Anterior (A), posterior (P), dorsal (D) and ventral (V) axes are indicated by double-headed arrows.

Fig. 3.

Fig. 3.

Patterning the third pharyngeal pouch. (A) At E10.5, Gcm2 expression (blue) marks the parathyroid domain within the third pouch, Bmp4 (orange) is expressed at ventral tip of the pouch and adjacent mesenchyme, and Shh (green) expression is detected in the pharynx but is excluded from the pouch. Neural crest cells (NCCs; purple/light blue/orange) surround the pouch and some express regionalized markers (Bmp4, orange; patched, light blue). (B) By E11.25, Foxn1 and Bmp4 expression (red) spreads dorsally (arrows) towards the Gcm2-expressing parathyroid domain (blue). (C) By E11.5, the third pouch epithelial cells express either Foxn1 and Bmp4 (red) or Gcm2 (blue). Signals from adjacent NCCs refine the position of the border between domains (arrows). (D) In situ hybridization for Gcm2 (top) demonstrates its proximal-dorsal-anterior-restricted expression domain at E10.5. Analysis of Bmp4lacZ mice (bottom) demonstrates Bmp4 expression at the ventral tip of the pouch endoderm and in the adjacent mesenchyme (asterisk) at this stage. (E) Foxn1 in situ hybridization (top) and Bmp4lacZ expression (bottom) at the distal-ventral tip of E11.25 primordium. (F) In situ hybridization for Gcm2 (top) and Foxn1 (bottom) on adjacent sections show non-overlapping expression at E11.5. In D-F, third pouch endoderm is outlined by dashed line. All data panels are sagittal sections oriented with dorsal on the left and ventral on the right. Panels in F included with permission (Foster et al., 2010).

Fig. 4.

Fig. 4.

Thymus-parathyroid morphogenesis. (A) Between E11.5 and E11.75, the third pouch-derived primordia, containing the thymus (red) and parathyroid (blue) domains, detach from the endoderm of the pharynx (endo) and the surface ectoderm (ecto) via apoptosis (black dots), with pharyngeal separation initiated a few hours before ectodermal separation. (B) At E12.5, the parathyroids (blue) have separated from thymus lobes (red). Note the slight temporal difference between the left and right sides (see Box 3). (C) At E13.5, the thymus lobes have migrated caudally, whereas the parathyroids are lateral to the thyroid (purple), with small parathyroid remnants between the parathyroids and thymus lobes. (D) The primordial attachment point to the pharynx at E11.5 spans Gcm2-positive (blue) and Gcm2-negative cells (blue and black arrows, respectively). The primordium (p) and pharynx (ph) are indicated. Dashed line outlines the primordium and its attachment to the pharynx. (E) At E12.0, a mesenchymal `wedge' (arrow; labeled with phalloidin in green) adjacent to the thymus-parathyroid (th-pt) border of the primordium (outlined by dotted line) can be observed. (F) By E13.5, a transverse hematoxylin and eosin-stained paraffin section shows that the parathyroid (pt) is located lateral to the thyroid (ty).

Fig. 5.

Fig. 5.

Consequences of disrupted morphogenesis. Examples of mouse mutants with defects in organ detachment, separation or migration. All panels are transverse hematoxylin and eosin-stained sections. (A) Abnormal pharynx detachment. At E12.5 of normal development, detachment is complete (top), but in Splotch mutants (Pax3Sp/Sp; bottom) the primordium remains attached by a thin cord of endoderm (arrow). (B) Persistent pharynx attachment. In newborn Wnt1Cre;Hoxa3fx/null mutants persistent attachment (arrows) is observed. A similar section level of a wild-type mouse is shown; the thymus is in a more posterior section. (C) Delayed organ separation. Separation of the parathyroid and thymus is complete by E12.5 of normal development, but not in Foxg1Cre;Bmp4loxp/null mutants. (D) Failed organ migration. In Wnt1Cre;ephrinB2loxp/null mutants, the thymus lobes (arrows) are ectopically located in a more anterior position than in wild type. A similar section level is shown for wild type; the thymus cannot be seen as it is in a more posterior section. es, esophagus; p, primordium; ph, pharynx; pt, parathyroid; th, thymus; tr, trachea. Images in A and B included with permission (Griffith et al., 2009; Chen et al., 2010).

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