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Glucocorticoids play a key role in circadian cell cycle rhythms.

Dickmeis T, Lahiri K, Nica G, Vallone D, Santoriello C, Neumann CJ, Hammerschmidt M, Foulkes NS - PLoS Biol. (2007)

Bottom Line: We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity.Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level.Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Germany.

ABSTRACT
Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary-adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.

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Reduction or Absence of the Pituitary Corticotrope Lineage Results in Attenuated Cell Cycle Rhythms(A) Expression of pituitary markers in rx3 mutants. Whole-mount in situ hybridizations for pit1, growth hormone (gh), prolactin (prl), the glycoprotein hormone alpha subunit (α-gsu), and proopiomelanocortin (pomc) (6 dpf), with ventral views through the jaw cartilages, rostral up. Domains of pomc expression are indicated by arrows (arcuate nucleus), arrowheads (anterior pituitary), and asterisks (posterior pituitary). strong, strong rx3 mutants; weak, weak rx3 mutants; wildtype, wild-type siblings.(B–D) Quantification of BrdU incorporation in the lia (B), aal (C), and pit1 (D) mutants. Mean numbers of BrdU-positive nuclei determined as described in Figure 1 are indicated for each time point for mutants (blue) and siblings (red). Error bars show the 95% confidence interval of the mean; asterisks indicate statistical differences between mutant and wild-type values as determined by the Mann-Whitney test: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Pooled results from two (B), five (C), and four (D) independent experiments are shown.(E) Scheme illustrating the pituitary lineages that are lacking (bracketed) in different pituitary mutants: lia and pia mutants lack all pituitary lineages. aal retains the lactotropes and lacks all other lineages. In pit1, only gonadotropes and corticotropes/melanotropes are present, and lactotropes, thyrotropes, and somatotropes are absent.
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pbio-0050078-g003: Reduction or Absence of the Pituitary Corticotrope Lineage Results in Attenuated Cell Cycle Rhythms(A) Expression of pituitary markers in rx3 mutants. Whole-mount in situ hybridizations for pit1, growth hormone (gh), prolactin (prl), the glycoprotein hormone alpha subunit (α-gsu), and proopiomelanocortin (pomc) (6 dpf), with ventral views through the jaw cartilages, rostral up. Domains of pomc expression are indicated by arrows (arcuate nucleus), arrowheads (anterior pituitary), and asterisks (posterior pituitary). strong, strong rx3 mutants; weak, weak rx3 mutants; wildtype, wild-type siblings.(B–D) Quantification of BrdU incorporation in the lia (B), aal (C), and pit1 (D) mutants. Mean numbers of BrdU-positive nuclei determined as described in Figure 1 are indicated for each time point for mutants (blue) and siblings (red). Error bars show the 95% confidence interval of the mean; asterisks indicate statistical differences between mutant and wild-type values as determined by the Mann-Whitney test: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Pooled results from two (B), five (C), and four (D) independent experiments are shown.(E) Scheme illustrating the pituitary lineages that are lacking (bracketed) in different pituitary mutants: lia and pia mutants lack all pituitary lineages. aal retains the lactotropes and lacks all other lineages. In pit1, only gonadotropes and corticotropes/melanotropes are present, and lactotropes, thyrotropes, and somatotropes are absent.

Mentions: The hypothalamic–pituitary axis is another endocrine pathway with a crucial role in the control of cell proliferation that shows circadian variations of activity [37]. We examined expression of a set of specific pituitary cell-lineage markers in the rx3 mutants: The transcription factor pit1 [38], growth hormone, gh [39], prolactin, prl [39], and glycoprotein hormone alpha subunit, α-gsu [38]. Expression of these markers is equivalent in rx3 mutants of both alleles when compared with their wild-type siblings (Figure 3A). Thus, the somatotrope (gh), lactotrope (prl), and gonadotrope/thyrotrope (α-gsu) lineages appear to be normally formed in the strong rx3 mutants. However, for the corticotrope/melanotrope lineage marker proopiomelanocortin (pomc, [39]), two expression domains show a marked reduction in strong allele rx3 mutants. The anterior pituitary domain is strongly reduced (arrowhead), and the expression corresponding to the β-endorphin/MSHα synthesizing cells of the arcuate nucleus ([40], arrow) is essentially absent, whereas the posterior pituitary expression domain (asterisk) appears normal. All these domains have a wild-type–like appearance in the weak allele mutant larvae (Figure 3A).


Glucocorticoids play a key role in circadian cell cycle rhythms.

Dickmeis T, Lahiri K, Nica G, Vallone D, Santoriello C, Neumann CJ, Hammerschmidt M, Foulkes NS - PLoS Biol. (2007)

Reduction or Absence of the Pituitary Corticotrope Lineage Results in Attenuated Cell Cycle Rhythms(A) Expression of pituitary markers in rx3 mutants. Whole-mount in situ hybridizations for pit1, growth hormone (gh), prolactin (prl), the glycoprotein hormone alpha subunit (α-gsu), and proopiomelanocortin (pomc) (6 dpf), with ventral views through the jaw cartilages, rostral up. Domains of pomc expression are indicated by arrows (arcuate nucleus), arrowheads (anterior pituitary), and asterisks (posterior pituitary). strong, strong rx3 mutants; weak, weak rx3 mutants; wildtype, wild-type siblings.(B–D) Quantification of BrdU incorporation in the lia (B), aal (C), and pit1 (D) mutants. Mean numbers of BrdU-positive nuclei determined as described in Figure 1 are indicated for each time point for mutants (blue) and siblings (red). Error bars show the 95% confidence interval of the mean; asterisks indicate statistical differences between mutant and wild-type values as determined by the Mann-Whitney test: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Pooled results from two (B), five (C), and four (D) independent experiments are shown.(E) Scheme illustrating the pituitary lineages that are lacking (bracketed) in different pituitary mutants: lia and pia mutants lack all pituitary lineages. aal retains the lactotropes and lacks all other lineages. In pit1, only gonadotropes and corticotropes/melanotropes are present, and lactotropes, thyrotropes, and somatotropes are absent.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC1828142&req=5

pbio-0050078-g003: Reduction or Absence of the Pituitary Corticotrope Lineage Results in Attenuated Cell Cycle Rhythms(A) Expression of pituitary markers in rx3 mutants. Whole-mount in situ hybridizations for pit1, growth hormone (gh), prolactin (prl), the glycoprotein hormone alpha subunit (α-gsu), and proopiomelanocortin (pomc) (6 dpf), with ventral views through the jaw cartilages, rostral up. Domains of pomc expression are indicated by arrows (arcuate nucleus), arrowheads (anterior pituitary), and asterisks (posterior pituitary). strong, strong rx3 mutants; weak, weak rx3 mutants; wildtype, wild-type siblings.(B–D) Quantification of BrdU incorporation in the lia (B), aal (C), and pit1 (D) mutants. Mean numbers of BrdU-positive nuclei determined as described in Figure 1 are indicated for each time point for mutants (blue) and siblings (red). Error bars show the 95% confidence interval of the mean; asterisks indicate statistical differences between mutant and wild-type values as determined by the Mann-Whitney test: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Pooled results from two (B), five (C), and four (D) independent experiments are shown.(E) Scheme illustrating the pituitary lineages that are lacking (bracketed) in different pituitary mutants: lia and pia mutants lack all pituitary lineages. aal retains the lactotropes and lacks all other lineages. In pit1, only gonadotropes and corticotropes/melanotropes are present, and lactotropes, thyrotropes, and somatotropes are absent.
Mentions: The hypothalamic–pituitary axis is another endocrine pathway with a crucial role in the control of cell proliferation that shows circadian variations of activity [37]. We examined expression of a set of specific pituitary cell-lineage markers in the rx3 mutants: The transcription factor pit1 [38], growth hormone, gh [39], prolactin, prl [39], and glycoprotein hormone alpha subunit, α-gsu [38]. Expression of these markers is equivalent in rx3 mutants of both alleles when compared with their wild-type siblings (Figure 3A). Thus, the somatotrope (gh), lactotrope (prl), and gonadotrope/thyrotrope (α-gsu) lineages appear to be normally formed in the strong rx3 mutants. However, for the corticotrope/melanotrope lineage marker proopiomelanocortin (pomc, [39]), two expression domains show a marked reduction in strong allele rx3 mutants. The anterior pituitary domain is strongly reduced (arrowhead), and the expression corresponding to the β-endorphin/MSHα synthesizing cells of the arcuate nucleus ([40], arrow) is essentially absent, whereas the posterior pituitary expression domain (asterisk) appears normal. All these domains have a wild-type–like appearance in the weak allele mutant larvae (Figure 3A).

Bottom Line: We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity.Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level.Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Germany.

ABSTRACT
Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary-adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.

Show MeSH
Related in: MedlinePlus