| 1. |
- Andersson, Louise, 1979, et al.
(författare)
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Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage.
- 2011
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:3, s. 1154-64
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4(-/-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A- and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important.
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| 2. |
- Fagman, Henrik, 1975, et al.
(författare)
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The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning.
- 2007
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:3, s. 276-85
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid dysgenesis is the major cause of congenital hypothyroidism in humans. The underlying molecular mechanism is in most cases unknown, but the frequent co-incidence of cardiac anomalies suggests that the thyroid morphogenetic process may depend on proper cardiovascular development. The T-box transcription factor TBX1, which is the most probable gene for the 22q11 deletion syndrome (22q11DS/DiGeorge syndrome/velo-cardio-facial syndrome), has emerged as a central player in the coordinated formation of organs and tissues derived from the pharyngeal apparatus and the adjacent secondary heart field from which the cardiac outflow tract derives. Here, we show that Tbx1 impacts greatly on the developing thyroid gland, although it cannot be detected in the thyroid primordium at any embryonic stage. Specifically, in Tbx1-/- mice, the downward translocation of Titf1/Nkx2.1-expressing thyroid progenitor cells is much delayed. In late mutant embryos, the thyroid fails to form symmetric lobes but persists as a single mass approximately one-fourth of the normal size. The hypoplastic gland mostly attains a unilateral position resembling thyroid hemiagenesis. The data further suggest that failure of the thyroid primordium to re-establish contact with the aortic sac is a key abnormality preventing normal growth of the midline anlage along the third pharyngeal arch arteries. In normal development, this interaction may be facilitated by Tbx1-expressing mesenchyme filling the gap between the pharyngeal endoderm and the detached thyroid primordium. The findings indicate that Tbx1 regulates intermediate steps of thyroid development by a non-cell-autonomous mechanism. Thyroid dysgenesis related to Tbx1 inactivation may explain an overrepresentation of hypothyroidism occurring in patients with the 22q11DS.
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| 3. |
- Westerlund, Jessica, 1977, et al.
(författare)
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Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia.
- 2008
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Ingår i: Developmental dynamics : an official publication of the American Association of Anatomists. - : Wiley. - 1058-8388. ; 237:12, s. 3820-9
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Tidskriftsartikel (refereegranskat)abstract
- The LIM homeodomain transcription factor 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 and 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. Together, these findings suggest that Isl1 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 be relevant also in cancer developed from the mature C-cell.
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| 4. |
- Westerlund, Jessica, 1977, et al.
(författare)
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Misguided migration of C cell precursors to extra-thyroidal locations related to defective pharyngeal pouch development in Shh deficient mice
- 2013
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Ingår i: Cell & Developmental Biology. - 2168-9296. ; 2:4, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- A possible role of Sonic hedgehog (Shh) in recruitment of C cell precursors to the ultimobranchial body (UB) and embryonic thyroid was investigated in Shh-/- mice. Nkx2.1 and Foxa2 co-expression distinguished UB originating in the fourth pharyngeal pouch from other derivatives of pharyngeal endoderm. In mutants UB formed a single structure that failed to bud and instead of fusing with the midline thyroid primordium adhered to the thymic rudiments. Mature C cells appeared in the UB remnant and ectopically in the thymic parenchyma, foregut endoderm and trachea. Thyroid did not contain C cells except minute numbers close to the tracheal interface. Tracing progeny in Shh-CRE/Rosa26R mice showed the vast majority of both UB and thyroid progenitors derived from Shh negative endoderm, but Shh expressing cells appeared in both thyroid primordia before fusion of the two. The findings indicate that Shh determines the endoderm territory for C cell differentiation and guides the migration of C cell precursors into the thyroid, presumably by regulating the separation of glandular domains in the pharyngeal pouch endoderm. A cell-autonomous role of Shh in thyroid morphogenesis is suggested.
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| 5. |
- Westerlund, Jessica, 1977
(författare)
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Transcriptional regulation of thyroid development possible interplay of endoderm- and mesoderm-derived morphogenetic signals
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congenital hypothyroidism (CH) affects 1 in 3000 children and is the major cause of treatable mental retardation. Most cases are due to malformations of the gland, collectively named thyroid dysgenesis. The disease results from defective thyroid organogenesis during embryonic life. However, the molecular mechanisms of pathogenesis are largely unknown. In recent years, identification and functional analysis of thyroid developmental genes in murine models have indicated that both cell-autonomous and non-cellautonomous mechanisms, involving the thyroid progenitors themselves and the surrounding embryonic tissues, respectively, are of importance. In this thesis, four important morphogenetic regulatory molecules were investigated for novel putative functions in mouse thyroid development. In paper I, the thyroid expression and function of the T-box transcription factor Tbx1 were examined in wild-type and Tbx1 null mutant mouse embryos. Tbx1 immunoreactivty was present in the splanchic mesoderm adjacent to the thyroid but not in the thyroid progenitors. The thyroid of Tbx1 deficient embryos was severely dysplastic resembling hemiagenesis and lacked C-cellls. It was further evidenced that the Tbx1-/- thyroid phenotype was related to delayed budding and failure of the disclosed thyroid rudiment to establish contact with embryonic vessels of the cardiac outflow tract. The LIM homeodomain transcription factor Isl1 was found to be expressed in both thyroid progenitors and surrounding mesenchyme (paper II). The Isl1 expression pattern was altered in a distinct spatiotemporal manner during the different developmental steps (budding, migration and fusion of the thyroid primordia). However, thyroid specification was not affected in Isl1 null mutants. In late development Isl1 identified the C-cell precursors, but Isl1 was largely down-regulated in mature adult C-cells. In addition, Isl1 transcript was detected in human medullary thyroid cancer. In paper III, the forkhead transcription factor Foxa2 was found to be an embryonic marker of pharyngeal endoderm, lateral thyroid anlagen (ultimobranchial bodies) and C-cells. The Foxa2 expression was maintained in adult C-cells. However, Foxa2 was specifically excluded from the follicular progenitors in the median thyroid bud, and was not expressed in the thyroid follicles. Foxa2 and calcitonin expression were employed to investigate the origin and fate of C-cell precursors in mouse embryos deficient of the secreted morphogen Sonic hedgehog (Shh) (paper IV). This showed that C-cell precursors did not colonize the embryonic thyroid but were aberrantly located in the pharyngeal endoderm and other endoderm derivatives. The Shh-/- phenotype was linked to impaired fusion of thyroid primordia, primarily caused by failure of the ultimobranchial bodies to bud from the fourth pharyngeal pouch. Paper IV also revealed that genetically fate mapped Shh expressing endoderm progenitors were largely excluded from the thyroid primordia. However, Shh was neo-expressed in a subset of follicular progenitors in late development of the prospective thyroid lobes. Taken together, the results of this thesis identify Tbx1 and Shh as novel regulators of mammalian thyroid organogenesis. This is likely manufactured in part by morphogenetic mechanisms superimposing on the development of the entire pharyngeal apparatus and also cell-autonomous regulatory networks. Isl1 and Foxa2 are proven to be novel embryonic markers of C-cell precursors. Collectively, the data support the hypothesis of an endoderm origin of mouse thyroid C-cells.
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