TOPIC: Genes involved in early thyroid development
Title: Expression of Islet1 in thyroid deve
lopment related to budding, migration, and fusion of primordia.
Authors: Westerlund J, Andersson L, Carlsson T, Zoppoli P, Fagman H, & Nilsson M.
Reference: Developmental Dynamics 237, 3820-3829, 2008
The thyroid is populated by two endocrine cell types that have different embryonic origins. The follicular cell progenitors, that differentiate into thyroxine-producing cells, are specified in the definitive anterior endoderm forming the thyroid diverticulum or bud, which soon thereafter detaches from the pharyngeal floor and moves to the final position of the gland. C-cell precursors derive from the neural crest and, eventually, enter the thyroid gland by fusion of the midline diverticulum with the lateral thyroid primordia or ultimobranchial bodies that pinch off from the most distal pouch of the pharyngeal arches. Budding and migration of the midline anlage requires the cooperation of transcription factors, namely Nkx2.1 (TTF-1), Foxe1 (TTF-2), Pax8, & Hhex. Transcription factors regulating pharyngeal arch development (e.g., Hox, Eya1) also contribute to the formation of the ultimobranchial bodies. Nkx2.1 is the only transcription factor so far known to be expressed in both the thyroid diverticulum & ultimobranchial bodies. Recent findings indicate that Nkx2.1 is required for the survival of both follicular and C-cell progenitors. Islet 1 (Isl1) is a LIM homeodomain transcription factor originally proven to be necessary for differentiation of exocrine & endocrine cells in developing pancreas. In addition, Isl1 deficiency causes apoptosis in the pharyngeal endoderm, accompanied by severe malformations of heart & cardiac outflow tract that lead to embryonic lethality around E10.5.
The role of Isl1 was investigated in mouse thyroid organogenesis. All progenitor cells of the midline thyroid diverticulum and lateral primordia (ultimobranchial bodies) expressed Isl1. This pattern persisted until the growing anlagen fused at embryonic day (E) 13.5. In Isl1 null mutants, thyroid progenitors expressing Nkx2.1 & Pax8 were readily specified in the anterior endoderm but the size of the thyroid rudiment was reduced. In late development, only immature C-cells expressed Isl1. In the adult gland, the number of Isl1 cells was small compared with cells expressing calcitonin. Analysis of microarray profiles indicated a higher level of Isl1 expression in medullary thyroid carcinomas than in tumors derived from follicular cells.
Taken together, these findings suggest that Islet 1 may be a novel regulator of thyroid development before terminal differentiation of the endocrine cell types. Isl1 is an embryonic C-cell precursor marker that may also be relevant in cancer developing from the mature C-cells.
This study establishes or reinforces concepts related to thyroid development which may have important connexion with the etiopathogeny of thyroid dysgenesis and thyroid cancer.
- Dual embryological origin of the thyroid gland. The study identifies Isl1 as a transcriptional regulator of both endocrine cell types (follicular cells & C-cells) in thyroid gland organogenesis.
- Close developmental relationships between the thyroid and the heart. Isl1 is a survival factor to embryonic progenitor cells. Isl1 null mice die at approximately E10.5 because of severe cardiovascular malformations related to the lack of Isl1-expressing cardiogenic progenitor cells populating the embryonic heart. Together with recent findings showing a role for cardiac mesoderm in early thyroid development, this provides a rationale for the clinical reports showing a high prevalence of cardiac malformations in children with congenital hypothyroidism caused by thyroid dysgenesis.
- Is Isl1 a marker of C-cell malignancy? Isl1 cells are scarce in comparison with the total number of C-cells. This may designate a subpopulation of C-cells that maintain progenitor properties in adult life. Transcription profiles of medullary thyroid cancer demonstrate that expression levels of Isl1 is consistently higher in medullary than papillary cancer. The expression of Isl1 in medullary thyroid cancer might thus reflect recapitulation of some of the embryonic properties of the ancestral cell. In this respect, it is interesting to note that Isl1 was recently shown to be a novel marker of pancreatic endocrine cancer.
Summary and commentary prepared by Gilbert Vassart (Related to Chapters 1 & 18 of TDM)