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ZBTB20 is required for anterior pituitary development and lactotrope specification.

Cao D, Ma X, Cai J, Luan J, Liu AJ, Yang R, Cao Y, Zhu X, Zhang H, Chen YX, Shi Y, Shi GX, Zou D, Cao X, Grusby MJ, Xie Z, Zhang WJ - Nat Commun (2016)

Bottom Line: Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes.Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ.In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.

ABSTRACT
The anterior pituitary harbours five distinct hormone-producing cell types, and their cellular differentiation is a highly regulated and coordinated process. Here we show that ZBTB20 is essential for anterior pituitary development and lactotrope specification in mice. In anterior pituitary, ZBTB20 is highly expressed by all the mature endocrine cell types, and to some less extent by somatolactotropes, the precursors of prolactin (PRL)-producing lactotropes. Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes. In ZBTB20- mice, although lactotrope lineage commitment is normally initiated, somatolactotropes exhibit profound defects in lineage specification and expansion. Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ. In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro. In conclusion, our findings point to ZBTB20 as a critical regulator of anterior pituitary development and lactotrope specification.

No MeSH data available.


Related in: MedlinePlus

Hypopituitarism in global ZBTB20- mice.(a) Body weight of Zbtb20+/+ and Zbtb20−/− mice. n=11–20 per time point. Values represent mean±s.e.m. *P<0.05 versus +/+, **P<0.01 versus +/+ (Student's t-test.) (b) A general view (upper) and section (lower, H&E) of 21-day-old pituitaries from Zbtb20+/+ and Zbtb20−/− littermate. Zbtb20−/− mouse has normal sized posterior lobe (black outline), but a severely reduced anterior lobe.PL, posterior lobe of pituitary; AL, anterior lobe. Scale bar, 1 mm. (c) Uterus and ovaries from female mice (upper) and testes and epididymides from male mice (lower) are significantly reduced in 21-day-old Zbtb20−/− mice compared with wild-type controls. Scale bar, 1 mm. (d) Whole-mammary-gland mounts staining of 28-day-old Zbtb20+/+ and Zbtb20−/− littermate. The Zbtb20−/− mice displayed an impeded ductal elongation (black arrowhead). Scale bar, 1 mm. (e) Quantitative RT–PCR analysis of Igf-1 mRNA level in liver from Zbtb20+/+ and Zbtb20−/− mice. Results are presented as fold induction relative to mRNA level in wild-type mice. n=3 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test). (f) Circulating IGF-1 levels are detected by ELISA at P14 and P21. n=6 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test).
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f1: Hypopituitarism in global ZBTB20- mice.(a) Body weight of Zbtb20+/+ and Zbtb20−/− mice. n=11–20 per time point. Values represent mean±s.e.m. *P<0.05 versus +/+, **P<0.01 versus +/+ (Student's t-test.) (b) A general view (upper) and section (lower, H&E) of 21-day-old pituitaries from Zbtb20+/+ and Zbtb20−/− littermate. Zbtb20−/− mouse has normal sized posterior lobe (black outline), but a severely reduced anterior lobe.PL, posterior lobe of pituitary; AL, anterior lobe. Scale bar, 1 mm. (c) Uterus and ovaries from female mice (upper) and testes and epididymides from male mice (lower) are significantly reduced in 21-day-old Zbtb20−/− mice compared with wild-type controls. Scale bar, 1 mm. (d) Whole-mammary-gland mounts staining of 28-day-old Zbtb20+/+ and Zbtb20−/− littermate. The Zbtb20−/− mice displayed an impeded ductal elongation (black arrowhead). Scale bar, 1 mm. (e) Quantitative RT–PCR analysis of Igf-1 mRNA level in liver from Zbtb20+/+ and Zbtb20−/− mice. Results are presented as fold induction relative to mRNA level in wild-type mice. n=3 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test). (f) Circulating IGF-1 levels are detected by ELISA at P14 and P21. n=6 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test).

Mentions: To evaluate the potential role of ZBTB20 in pituitary biology, we first examined pituitary development and function in ZBTB20- mice. As previously described24, Zbtb20 global knockout mice were grossly indistinguishable from their control littermates at birth, but exhibited significant postnatal growth retardation, premature mortality and infertility, which are indicative of hypopituitarism. At the mixed genetic background of C57BL/6J and 129 Sv, more than half of homozygous mutants can survive up to 4 weeks, with a few to adulthood24. However, after backcrossed to C57BL/6J mice for 12 generations, a vast majority of mutant homozygotes died within 4 weeks of age. Therefore, we phenotypically analysed the mutant mice mainly within 3 weeks of age, when they were relatively healthy, however, with a dramatic reduction in body size and weight compared with littermate controls (Fig. 1a). At birth, there was no gross difference of pituitary between mutant and control littermates (Supplementary Fig. 1). From 1 week after birth, the mutant pituitaries were markedly smaller in size than littermate controls, thus they were only ∼50% of the normal weight at postnatal day 21 (P21; Fig. 1b). Of note, the hypoplasia was mainly observed in the anterior pituitaries from both male and female mutant mice, while their posterior lobes were not significantly affected. In addition, the female mutants also displayed profound hypoplasia in ovary and uterus (Fig. 1c). Whole mount of mammary glands revealed a severely impeded ductal elongation in 4-week-old female mice, while age-matched control mice displayed extensive ductal elongation and branching (Fig. 1d). The hypothalamus that control pituitary development and function was anatomically and histologically normal in mutant mice. Taken together, the above observed growth retardation, sexual infantilism and anterior pituitary hypoplasia strongly suggest that ZBTB20 disruption results in hypopituitary dwarfism.


ZBTB20 is required for anterior pituitary development and lactotrope specification.

Cao D, Ma X, Cai J, Luan J, Liu AJ, Yang R, Cao Y, Zhu X, Zhang H, Chen YX, Shi Y, Shi GX, Zou D, Cao X, Grusby MJ, Xie Z, Zhang WJ - Nat Commun (2016)

Hypopituitarism in global ZBTB20- mice.(a) Body weight of Zbtb20+/+ and Zbtb20−/− mice. n=11–20 per time point. Values represent mean±s.e.m. *P<0.05 versus +/+, **P<0.01 versus +/+ (Student's t-test.) (b) A general view (upper) and section (lower, H&E) of 21-day-old pituitaries from Zbtb20+/+ and Zbtb20−/− littermate. Zbtb20−/− mouse has normal sized posterior lobe (black outline), but a severely reduced anterior lobe.PL, posterior lobe of pituitary; AL, anterior lobe. Scale bar, 1 mm. (c) Uterus and ovaries from female mice (upper) and testes and epididymides from male mice (lower) are significantly reduced in 21-day-old Zbtb20−/− mice compared with wild-type controls. Scale bar, 1 mm. (d) Whole-mammary-gland mounts staining of 28-day-old Zbtb20+/+ and Zbtb20−/− littermate. The Zbtb20−/− mice displayed an impeded ductal elongation (black arrowhead). Scale bar, 1 mm. (e) Quantitative RT–PCR analysis of Igf-1 mRNA level in liver from Zbtb20+/+ and Zbtb20−/− mice. Results are presented as fold induction relative to mRNA level in wild-type mice. n=3 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test). (f) Circulating IGF-1 levels are detected by ELISA at P14 and P21. n=6 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test).
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Related In: Results  -  Collection

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f1: Hypopituitarism in global ZBTB20- mice.(a) Body weight of Zbtb20+/+ and Zbtb20−/− mice. n=11–20 per time point. Values represent mean±s.e.m. *P<0.05 versus +/+, **P<0.01 versus +/+ (Student's t-test.) (b) A general view (upper) and section (lower, H&E) of 21-day-old pituitaries from Zbtb20+/+ and Zbtb20−/− littermate. Zbtb20−/− mouse has normal sized posterior lobe (black outline), but a severely reduced anterior lobe.PL, posterior lobe of pituitary; AL, anterior lobe. Scale bar, 1 mm. (c) Uterus and ovaries from female mice (upper) and testes and epididymides from male mice (lower) are significantly reduced in 21-day-old Zbtb20−/− mice compared with wild-type controls. Scale bar, 1 mm. (d) Whole-mammary-gland mounts staining of 28-day-old Zbtb20+/+ and Zbtb20−/− littermate. The Zbtb20−/− mice displayed an impeded ductal elongation (black arrowhead). Scale bar, 1 mm. (e) Quantitative RT–PCR analysis of Igf-1 mRNA level in liver from Zbtb20+/+ and Zbtb20−/− mice. Results are presented as fold induction relative to mRNA level in wild-type mice. n=3 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test). (f) Circulating IGF-1 levels are detected by ELISA at P14 and P21. n=6 per time point. Values represent mean±s.e.m. *P<0.05, **P<0.01 (Student's t-test).
Mentions: To evaluate the potential role of ZBTB20 in pituitary biology, we first examined pituitary development and function in ZBTB20- mice. As previously described24, Zbtb20 global knockout mice were grossly indistinguishable from their control littermates at birth, but exhibited significant postnatal growth retardation, premature mortality and infertility, which are indicative of hypopituitarism. At the mixed genetic background of C57BL/6J and 129 Sv, more than half of homozygous mutants can survive up to 4 weeks, with a few to adulthood24. However, after backcrossed to C57BL/6J mice for 12 generations, a vast majority of mutant homozygotes died within 4 weeks of age. Therefore, we phenotypically analysed the mutant mice mainly within 3 weeks of age, when they were relatively healthy, however, with a dramatic reduction in body size and weight compared with littermate controls (Fig. 1a). At birth, there was no gross difference of pituitary between mutant and control littermates (Supplementary Fig. 1). From 1 week after birth, the mutant pituitaries were markedly smaller in size than littermate controls, thus they were only ∼50% of the normal weight at postnatal day 21 (P21; Fig. 1b). Of note, the hypoplasia was mainly observed in the anterior pituitaries from both male and female mutant mice, while their posterior lobes were not significantly affected. In addition, the female mutants also displayed profound hypoplasia in ovary and uterus (Fig. 1c). Whole mount of mammary glands revealed a severely impeded ductal elongation in 4-week-old female mice, while age-matched control mice displayed extensive ductal elongation and branching (Fig. 1d). The hypothalamus that control pituitary development and function was anatomically and histologically normal in mutant mice. Taken together, the above observed growth retardation, sexual infantilism and anterior pituitary hypoplasia strongly suggest that ZBTB20 disruption results in hypopituitary dwarfism.

Bottom Line: Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes.Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ.In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.

ABSTRACT
The anterior pituitary harbours five distinct hormone-producing cell types, and their cellular differentiation is a highly regulated and coordinated process. Here we show that ZBTB20 is essential for anterior pituitary development and lactotrope specification in mice. In anterior pituitary, ZBTB20 is highly expressed by all the mature endocrine cell types, and to some less extent by somatolactotropes, the precursors of prolactin (PRL)-producing lactotropes. Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes. In ZBTB20- mice, although lactotrope lineage commitment is normally initiated, somatolactotropes exhibit profound defects in lineage specification and expansion. Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ. In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro. In conclusion, our findings point to ZBTB20 as a critical regulator of anterior pituitary development and lactotrope specification.

No MeSH data available.


Related in: MedlinePlus