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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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Cell proliferation and p57 expression in thyroids at E9.5 and E15.5.Immunohistochemistry of Nkx2-1 (A, B, F, G, K, L, P, Q), BrdU (C, H, M, R), and p57 (E, J, O, T) in transverse sections from wild type mice (A–E and K–O) and Hes1−/− mice (F–J and P–T) at E9.5 (A–J) and E15.5 (K–T). Boxed areas were enlarged (B–E, G–J, L–O, Q–T). tr: trachea; thy: thyroid; ma: median anlage; to: tongue.
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pone-0016752-g006: Cell proliferation and p57 expression in thyroids at E9.5 and E15.5.Immunohistochemistry of Nkx2-1 (A, B, F, G, K, L, P, Q), BrdU (C, H, M, R), and p57 (E, J, O, T) in transverse sections from wild type mice (A–E and K–O) and Hes1−/− mice (F–J and P–T) at E9.5 (A–J) and E15.5 (K–T). Boxed areas were enlarged (B–E, G–J, L–O, Q–T). tr: trachea; thy: thyroid; ma: median anlage; to: tongue.

Mentions: We investigated four possible hypotheses for thyroid hypoplasia in Hes1−/− thyroids: 1) decreased proportion of proliferating cells in the developing thyroid, 2) increased proportion of apoptotic cells, 3) accelerated cell differentiation, and 4) decreased pool of progenitor cells from specification. To assess proliferation, we determined the ratio of BrdU-labelled Nkx2-1-positive cells over all Nkx2-1-positive cells. At E9.5, the proportion of Nkx2-1-positive cells labelled by BrdU was 4.6% in wild type thyroids (Figure 6A–D and Figure 7A) and 13.2% (p<0.001) in Hes1−/− thyroids (Figure 6F–I and Figure 7A). At E11.5, E13.5, and E15.5, this ratio was not significantly different between Hes1−/− and wild type thyroids (Figure 6K–N, P–S and Figure 7A). Neither did we find any evidence supporting a role for increased apoptosis in the thyroid hypoplasia (data not shown). Hes1−/− and wild type thyroids were not different regarding the time of appearance of TG and T4 immunostaining in thyrocytes or of CT immunostaining in C-cells. Thus, hormone-producing cells did not differentiate earlier in Hes1−/− than in wild type mice, in keeping with data on pancreas development [7]. In contrast, the number of Nkx2-1 positive progenitor cells was significantly lower in Hes1−/− thyroids than in wild type thyroids: at E9.5 in the median anlage by 42% (p<0.05) and at E11.5 in the ultimobranchial bodies by 73% (p<0.01), respectively (Figure 7B).


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)

Cell proliferation and p57 expression in thyroids at E9.5 and E15.5.Immunohistochemistry of Nkx2-1 (A, B, F, G, K, L, P, Q), BrdU (C, H, M, R), and p57 (E, J, O, T) in transverse sections from wild type mice (A–E and K–O) and Hes1−/− mice (F–J and P–T) at E9.5 (A–J) and E15.5 (K–T). Boxed areas were enlarged (B–E, G–J, L–O, Q–T). tr: trachea; thy: thyroid; ma: median anlage; to: tongue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045378&req=5

pone-0016752-g006: Cell proliferation and p57 expression in thyroids at E9.5 and E15.5.Immunohistochemistry of Nkx2-1 (A, B, F, G, K, L, P, Q), BrdU (C, H, M, R), and p57 (E, J, O, T) in transverse sections from wild type mice (A–E and K–O) and Hes1−/− mice (F–J and P–T) at E9.5 (A–J) and E15.5 (K–T). Boxed areas were enlarged (B–E, G–J, L–O, Q–T). tr: trachea; thy: thyroid; ma: median anlage; to: tongue.
Mentions: We investigated four possible hypotheses for thyroid hypoplasia in Hes1−/− thyroids: 1) decreased proportion of proliferating cells in the developing thyroid, 2) increased proportion of apoptotic cells, 3) accelerated cell differentiation, and 4) decreased pool of progenitor cells from specification. To assess proliferation, we determined the ratio of BrdU-labelled Nkx2-1-positive cells over all Nkx2-1-positive cells. At E9.5, the proportion of Nkx2-1-positive cells labelled by BrdU was 4.6% in wild type thyroids (Figure 6A–D and Figure 7A) and 13.2% (p<0.001) in Hes1−/− thyroids (Figure 6F–I and Figure 7A). At E11.5, E13.5, and E15.5, this ratio was not significantly different between Hes1−/− and wild type thyroids (Figure 6K–N, P–S and Figure 7A). Neither did we find any evidence supporting a role for increased apoptosis in the thyroid hypoplasia (data not shown). Hes1−/− and wild type thyroids were not different regarding the time of appearance of TG and T4 immunostaining in thyrocytes or of CT immunostaining in C-cells. Thus, hormone-producing cells did not differentiate earlier in Hes1−/− than in wild type mice, in keeping with data on pancreas development [7]. In contrast, the number of Nkx2-1 positive progenitor cells was significantly lower in Hes1−/− thyroids than in wild type thyroids: at E9.5 in the median anlage by 42% (p<0.05) and at E11.5 in the ultimobranchial bodies by 73% (p<0.01), respectively (Figure 7B).

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