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Hes1 is required for appropriate morphogenesis and differentiation during mouse thyroid gland development.

Carre A, Rachdi L, Tron E, Richard B, Castanet M, Schlumberger M, Bidart JM, Szinnai G, Polak M - PLoS ONE (2011)

Bottom Line: After fusion of thyroid anlages, hypoplastic Hes1(-/-) thyroids revealed a significantly decreased labelling area for T4 (-78%) and calcitonin (-65%) normalized to Nkx2-1 positive cells.Decreased T4-synthesis might be due to reduced Nis labelling area (-69%).These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells.

View Article: PubMed Central - PubMed

Affiliation: INSERM U845, Université Paris-Descartes, Paris, France.

ABSTRACT
Notch signalling plays an important role in endocrine development, through its target gene Hes1. Hes1, a bHLH transcriptional repressor, influences progenitor cell proliferation and differentiation. Recently, Hes1 was shown to be expressed in the thyroid and regulate expression of the sodium iodide symporter (Nis). To investigate the role of Hes1 for thyroid development, we studied thyroid morphology and function in mice lacking Hes1. During normal mouse thyroid development, Hes1 was detected from E9.5 onwards in the median anlage, and at E11.5 in the ultimobranchial bodies. Hes1(-/-) mouse embryos had a significantly lower number of Nkx2-1-positive progenitor cells (p<0.05) at E9.5 and at E11.5. Moreover, Hes1(-/-) mouse embryos showed a significantly smaller total thyroid surface area (-40 to -60%) compared to wild type mice at all study time points (E9.5-E16.5). In both Hes1(-/-) and wild type mouse embryos, most Nkx2-1-positive thyroid cells expressed the cell cycle inhibitor p57 at E9.5 in correlation with low proliferation index. In Hes1(-/-) mouse embryos, fusion of the median anlage with the ultimobranchial bodies was delayed by 3 days (E16.5 vs. E13.5 in wild type mice). After fusion of thyroid anlages, hypoplastic Hes1(-/-) thyroids revealed a significantly decreased labelling area for T4 (-78%) and calcitonin (-65%) normalized to Nkx2-1 positive cells. Decreased T4-synthesis might be due to reduced Nis labelling area (-69%). These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells.

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Thyroid hypoplasia in Hes1−/− embryos.A: Nkx2-1 staining at E9.5 (sagittal sections) and at E11.5, E13.5, E15.5, and E16.5 (transverse sections) in littermates. Total thyroid surface area (µm2) was quantified using Nkx2-1 staining at each embryonic stage, B: The results represent the surface area of three embryos per stage and per genotype. UB: ultimobranchial body; ma: median anlage; tr: trachea, oe: oesophagus. Student's test, * p<0.05 and ** p<0.01.
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pone-0016752-g002: Thyroid hypoplasia in Hes1−/− embryos.A: Nkx2-1 staining at E9.5 (sagittal sections) and at E11.5, E13.5, E15.5, and E16.5 (transverse sections) in littermates. Total thyroid surface area (µm2) was quantified using Nkx2-1 staining at each embryonic stage, B: The results represent the surface area of three embryos per stage and per genotype. UB: ultimobranchial body; ma: median anlage; tr: trachea, oe: oesophagus. Student's test, * p<0.05 and ** p<0.01.

Mentions: To determine the role for Hes1 in thyroid development, we investigated mice lacking functional Hes1 alleles. This well-characterized allele lacks the first 3 exons of the Hes1 gene, which encodes the bHLH domain of Hes1 [15]. Hes1 embryos die during fetal development, allowing examination of the morphology of the thyroid in wild-type and Hes1 mutants at the onset of endocrine function at E16.5 but not beyond. Nkx2-1 is expressed in undifferentiated thyrocytes as well as C-cells precursors in the median anlage and the ultimobranchial bodies from E9.5 onwards and remains expressed in both cell types after onset of endocrine function. Thus, we evaluated the size of the developing thyroid by measuring the surface area of Nkx2-1-positive cells at E9.5, E11.5, E13.5, E15.5 and E16.5. We compared at each stage three Hes1−/− and three wild type embryos (Figure 2A, B and C). At E9.5, we performed sagittal sections of embryos and we located the Nkx2-1 positive thyroid median anlage within the endoderm covering the tongue in analogy with previous work [1], [3] (Figure 2A). From E11.5 to E16.5, we performed transverse sections of embryos and we located the Nkx2-1 positive thyroid lobes in the typical lateral position on both sides of the trachea and larynx, and the isthmus connecting the two lobes by crossing the trachea in a pretracheal position (Figure 2A). In accordance with the general Nkx2-1 expression pattern, the tracheal epithelium showed also specific positive staining. At E9.5, the median anlage of Hes1 mutants was already significantly smaller than in wild type mice, the Nkx2-1-positive surface area being 36% smaller (p<0.05) (Figure 2B). At E11.5, the overall Nkx2-1-positive surface area of both thyroid anlages in Hes1−/− mice was 65% (p<0.01) smaller than in the wild type mice (median anlage: −36%; ultimobranchial bodies: −83%) (Figure 2B). At E13.5, E15.5, and E16.5, the thyroids of Hes1−/− mice were 65% (p<0.05), 34% (p<0.01), and 50% (p<0.01) smaller, respectively, than those of wild type mice (Figure 2C). Thyroid size of heterozygous Hes1+/− thyroids was normal compared to wild-type littermates, but was significantly bigger than Hes1−/− thyroids (p<0.01) (data not shown). This significant reduction of thyroid size at all stages was not paralleled by a general hypotrophy or reduction of the overall body size of Hes1−/− mutants.


Hes1 is required for appropriate morphogenesis and differentiation during mouse thyroid gland development.

Carre A, Rachdi L, Tron E, Richard B, Castanet M, Schlumberger M, Bidart JM, Szinnai G, Polak M - PLoS ONE (2011)

Thyroid hypoplasia in Hes1−/− embryos.A: Nkx2-1 staining at E9.5 (sagittal sections) and at E11.5, E13.5, E15.5, and E16.5 (transverse sections) in littermates. Total thyroid surface area (µm2) was quantified using Nkx2-1 staining at each embryonic stage, B: The results represent the surface area of three embryos per stage and per genotype. UB: ultimobranchial body; ma: median anlage; tr: trachea, oe: oesophagus. Student's test, * p<0.05 and ** p<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045378&req=5

pone-0016752-g002: Thyroid hypoplasia in Hes1−/− embryos.A: Nkx2-1 staining at E9.5 (sagittal sections) and at E11.5, E13.5, E15.5, and E16.5 (transverse sections) in littermates. Total thyroid surface area (µm2) was quantified using Nkx2-1 staining at each embryonic stage, B: The results represent the surface area of three embryos per stage and per genotype. UB: ultimobranchial body; ma: median anlage; tr: trachea, oe: oesophagus. Student's test, * p<0.05 and ** p<0.01.
Mentions: To determine the role for Hes1 in thyroid development, we investigated mice lacking functional Hes1 alleles. This well-characterized allele lacks the first 3 exons of the Hes1 gene, which encodes the bHLH domain of Hes1 [15]. Hes1 embryos die during fetal development, allowing examination of the morphology of the thyroid in wild-type and Hes1 mutants at the onset of endocrine function at E16.5 but not beyond. Nkx2-1 is expressed in undifferentiated thyrocytes as well as C-cells precursors in the median anlage and the ultimobranchial bodies from E9.5 onwards and remains expressed in both cell types after onset of endocrine function. Thus, we evaluated the size of the developing thyroid by measuring the surface area of Nkx2-1-positive cells at E9.5, E11.5, E13.5, E15.5 and E16.5. We compared at each stage three Hes1−/− and three wild type embryos (Figure 2A, B and C). At E9.5, we performed sagittal sections of embryos and we located the Nkx2-1 positive thyroid median anlage within the endoderm covering the tongue in analogy with previous work [1], [3] (Figure 2A). From E11.5 to E16.5, we performed transverse sections of embryos and we located the Nkx2-1 positive thyroid lobes in the typical lateral position on both sides of the trachea and larynx, and the isthmus connecting the two lobes by crossing the trachea in a pretracheal position (Figure 2A). In accordance with the general Nkx2-1 expression pattern, the tracheal epithelium showed also specific positive staining. At E9.5, the median anlage of Hes1 mutants was already significantly smaller than in wild type mice, the Nkx2-1-positive surface area being 36% smaller (p<0.05) (Figure 2B). At E11.5, the overall Nkx2-1-positive surface area of both thyroid anlages in Hes1−/− mice was 65% (p<0.01) smaller than in the wild type mice (median anlage: −36%; ultimobranchial bodies: −83%) (Figure 2B). At E13.5, E15.5, and E16.5, the thyroids of Hes1−/− mice were 65% (p<0.05), 34% (p<0.01), and 50% (p<0.01) smaller, respectively, than those of wild type mice (Figure 2C). Thyroid size of heterozygous Hes1+/− thyroids was normal compared to wild-type littermates, but was significantly bigger than Hes1−/− thyroids (p<0.01) (data not shown). This significant reduction of thyroid size at all stages was not paralleled by a general hypotrophy or reduction of the overall body size of Hes1−/− mutants.

Bottom Line: After fusion of thyroid anlages, hypoplastic Hes1(-/-) thyroids revealed a significantly decreased labelling area for T4 (-78%) and calcitonin (-65%) normalized to Nkx2-1 positive cells.Decreased T4-synthesis might be due to reduced Nis labelling area (-69%).These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells.

View Article: PubMed Central - PubMed

Affiliation: INSERM U845, Université Paris-Descartes, Paris, France.

ABSTRACT
Notch signalling plays an important role in endocrine development, through its target gene Hes1. Hes1, a bHLH transcriptional repressor, influences progenitor cell proliferation and differentiation. Recently, Hes1 was shown to be expressed in the thyroid and regulate expression of the sodium iodide symporter (Nis). To investigate the role of Hes1 for thyroid development, we studied thyroid morphology and function in mice lacking Hes1. During normal mouse thyroid development, Hes1 was detected from E9.5 onwards in the median anlage, and at E11.5 in the ultimobranchial bodies. Hes1(-/-) mouse embryos had a significantly lower number of Nkx2-1-positive progenitor cells (p<0.05) at E9.5 and at E11.5. Moreover, Hes1(-/-) mouse embryos showed a significantly smaller total thyroid surface area (-40 to -60%) compared to wild type mice at all study time points (E9.5-E16.5). In both Hes1(-/-) and wild type mouse embryos, most Nkx2-1-positive thyroid cells expressed the cell cycle inhibitor p57 at E9.5 in correlation with low proliferation index. In Hes1(-/-) mouse embryos, fusion of the median anlage with the ultimobranchial bodies was delayed by 3 days (E16.5 vs. E13.5 in wild type mice). After fusion of thyroid anlages, hypoplastic Hes1(-/-) thyroids revealed a significantly decreased labelling area for T4 (-78%) and calcitonin (-65%) normalized to Nkx2-1 positive cells. Decreased T4-synthesis might be due to reduced Nis labelling area (-69%). These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells.

Show MeSH
Related in: MedlinePlus