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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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Hes1 expression during thyroid development.A: RT-QPCR analysis of Hes1 mRNA expression in embryonic and adult thyroids.Hes1 expression increased significantly from E13.5 until E18.5 (p<0.05). B-T: Immunohistochemistry for Hes1 and Nkx2-1 in whole embryos at E9.5 and E11.5 (sagittal sections) (B–J). At E9.5, Nkx2-1 stained the median thyroid anlage evaginating of the endoderm. At E11.5, Nkx2-1 stained the median anlage along the aortic sac. At E11.5, Nkx2-1 marked the symmetrical ultimobranchial bodies from the endoderm of the fourth pharyngeal pouch. Hes1 co-localised with Nkx2-1 cells in the median anlage and in the ultimobranchial bodies. At E13.5, immunohistochemistry for Hes1, Nkx2-1 and Mash1 is shown in dissected thyroids at E13.5 (K, L, O, P, S). In dissected thyroids at E17.5 (M, N, Q, R) Hes1/TG, and CT/E-cadherin co-labelling was analysed in adjacent sections. H, I, J, Q, R, S represent enlarged areas. Hes1 is expressed in progenitors of and in mature thyrocytes and C-cells. ma: median anlage; UB: ultimobranchial body, as: aortic sac.
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pone-0016752-g001: Hes1 expression during thyroid development.A: RT-QPCR analysis of Hes1 mRNA expression in embryonic and adult thyroids.Hes1 expression increased significantly from E13.5 until E18.5 (p<0.05). B-T: Immunohistochemistry for Hes1 and Nkx2-1 in whole embryos at E9.5 and E11.5 (sagittal sections) (B–J). At E9.5, Nkx2-1 stained the median thyroid anlage evaginating of the endoderm. At E11.5, Nkx2-1 stained the median anlage along the aortic sac. At E11.5, Nkx2-1 marked the symmetrical ultimobranchial bodies from the endoderm of the fourth pharyngeal pouch. Hes1 co-localised with Nkx2-1 cells in the median anlage and in the ultimobranchial bodies. At E13.5, immunohistochemistry for Hes1, Nkx2-1 and Mash1 is shown in dissected thyroids at E13.5 (K, L, O, P, S). In dissected thyroids at E17.5 (M, N, Q, R) Hes1/TG, and CT/E-cadherin co-labelling was analysed in adjacent sections. H, I, J, Q, R, S represent enlarged areas. Hes1 is expressed in progenitors of and in mature thyrocytes and C-cells. ma: median anlage; UB: ultimobranchial body, as: aortic sac.

Mentions: Hes1 mRNA expression was significantly increased in thyroid glands from E13.5 to E18.5 embryos (p<0.05 E13.5 vs. E18.5) (Figure 1A). Then, we studied expression of Hes1 on mRNA and protein level by use of in situ hybridization (ISH) and of a specific antibody on wild-type and Hes1−/− embryos (Figure S1). Hes1 protein was only expressed in a subset of Nkx2-1-positive precursors of the median anlage at E9.5, (Figure 1B, E, H) but was clearly expressed at E11.5 in both, the median anlage lining the aortic sac (Figure 1C, F, I) and in the ultimobranchial bodies in a lateral position (Figure 1D, G, J). Further, Hes1 positive cells were also present in the thyroid anlagen surrounding tissues (Figure 1E, F, G). To determine which cell types expressed Hes1, we investigated co-expression of Hes1 with antibodies against Nkx2-1, thyroglobulin (TG), calcitonin (CT), and Mash1. At E13.5, Hes1 was expressed in some Nkx2-1-positive cells (Figure 1K, O, S). From E15.5 to E18.5 and in adult glands, Hes1 showed nuclear staining in most Nkx2-1-positive (data not shown) and TG-producing thyrocytes within thyroid follicles (Figure 1M, N, Q). Hes1 was expressed at E13.5 in Mash1-positive cells (Figure 1L, P) and from E15.5 onwards in CT-producing C-cells (Figure 1R). This Hes1 expression profile in the developing as well as adult thyroid tissue suggested a role of Hes1 for differentiation and endocrine function of Nkx2-1-positive thyrocytes precursors as well as for Nkx2-1/Mash1-double-positive C-cell progenitors.


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)

Hes1 expression during thyroid development.A: RT-QPCR analysis of Hes1 mRNA expression in embryonic and adult thyroids.Hes1 expression increased significantly from E13.5 until E18.5 (p<0.05). B-T: Immunohistochemistry for Hes1 and Nkx2-1 in whole embryos at E9.5 and E11.5 (sagittal sections) (B–J). At E9.5, Nkx2-1 stained the median thyroid anlage evaginating of the endoderm. At E11.5, Nkx2-1 stained the median anlage along the aortic sac. At E11.5, Nkx2-1 marked the symmetrical ultimobranchial bodies from the endoderm of the fourth pharyngeal pouch. Hes1 co-localised with Nkx2-1 cells in the median anlage and in the ultimobranchial bodies. At E13.5, immunohistochemistry for Hes1, Nkx2-1 and Mash1 is shown in dissected thyroids at E13.5 (K, L, O, P, S). In dissected thyroids at E17.5 (M, N, Q, R) Hes1/TG, and CT/E-cadherin co-labelling was analysed in adjacent sections. H, I, J, Q, R, S represent enlarged areas. Hes1 is expressed in progenitors of and in mature thyrocytes and C-cells. ma: median anlage; UB: ultimobranchial body, as: aortic sac.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045378&req=5

pone-0016752-g001: Hes1 expression during thyroid development.A: RT-QPCR analysis of Hes1 mRNA expression in embryonic and adult thyroids.Hes1 expression increased significantly from E13.5 until E18.5 (p<0.05). B-T: Immunohistochemistry for Hes1 and Nkx2-1 in whole embryos at E9.5 and E11.5 (sagittal sections) (B–J). At E9.5, Nkx2-1 stained the median thyroid anlage evaginating of the endoderm. At E11.5, Nkx2-1 stained the median anlage along the aortic sac. At E11.5, Nkx2-1 marked the symmetrical ultimobranchial bodies from the endoderm of the fourth pharyngeal pouch. Hes1 co-localised with Nkx2-1 cells in the median anlage and in the ultimobranchial bodies. At E13.5, immunohistochemistry for Hes1, Nkx2-1 and Mash1 is shown in dissected thyroids at E13.5 (K, L, O, P, S). In dissected thyroids at E17.5 (M, N, Q, R) Hes1/TG, and CT/E-cadherin co-labelling was analysed in adjacent sections. H, I, J, Q, R, S represent enlarged areas. Hes1 is expressed in progenitors of and in mature thyrocytes and C-cells. ma: median anlage; UB: ultimobranchial body, as: aortic sac.
Mentions: Hes1 mRNA expression was significantly increased in thyroid glands from E13.5 to E18.5 embryos (p<0.05 E13.5 vs. E18.5) (Figure 1A). Then, we studied expression of Hes1 on mRNA and protein level by use of in situ hybridization (ISH) and of a specific antibody on wild-type and Hes1−/− embryos (Figure S1). Hes1 protein was only expressed in a subset of Nkx2-1-positive precursors of the median anlage at E9.5, (Figure 1B, E, H) but was clearly expressed at E11.5 in both, the median anlage lining the aortic sac (Figure 1C, F, I) and in the ultimobranchial bodies in a lateral position (Figure 1D, G, J). Further, Hes1 positive cells were also present in the thyroid anlagen surrounding tissues (Figure 1E, F, G). To determine which cell types expressed Hes1, we investigated co-expression of Hes1 with antibodies against Nkx2-1, thyroglobulin (TG), calcitonin (CT), and Mash1. At E13.5, Hes1 was expressed in some Nkx2-1-positive cells (Figure 1K, O, S). From E15.5 to E18.5 and in adult glands, Hes1 showed nuclear staining in most Nkx2-1-positive (data not shown) and TG-producing thyrocytes within thyroid follicles (Figure 1M, N, Q). Hes1 was expressed at E13.5 in Mash1-positive cells (Figure 1L, P) and from E15.5 onwards in CT-producing C-cells (Figure 1R). This Hes1 expression profile in the developing as well as adult thyroid tissue suggested a role of Hes1 for differentiation and endocrine function of Nkx2-1-positive thyrocytes precursors as well as for Nkx2-1/Mash1-double-positive C-cell progenitors.

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