Abstract
To understand the role of microRNAs (miRNAs) in pituitary development, a group of pituitary-specific miRNAs were identified, and Dicer1 was then conditionally knocked out using the Pitx2-Cre mouse, resulting in the loss of mature miRNAs in the anterior pituitary. The Pitx2-Cre/Dicer1 mutant mice demonstrate growth retardation, and the pituitaries are hypoplastic with an abnormal branching of the anterior lobe, revealing a role for microRNAs in pituitary development. Growth hormone, prolactin, and thyroid-stimulating hormone β-subunit expression were decreased in the Dicer1 mutant mouse, whereas proopiomelanocortin and luteinizing hormone β-subunit expression were normal in the mutant pituitary. Further analyses revealed decreased Pit-1 and increased Lef-1 expression in the mutant mouse pituitary, consistent with the repression of the Pit-1 promoter by Lef-1. Lef-1 directly targets and represses the Pit-1 promoter. miRNA-26b (miR-26b) was identified as targeting Lef-1 expression, and miR-26b represses Lef-1 in pituitary and non-pituitary cell lines. Furthermore, miR-26b up-regulates Pit-1 and growth hormone expression by attenuating Lef-1 expression in GH3 cells. This study demonstrates that microRNAs are critical for anterior pituitary development and that miR-26b regulates Pit-1 expression by inhibiting Lef-1 expression and may promote Pit-1 lineage differentiation during pituitary development.
MeSH terms
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Animals
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Cell Differentiation / physiology
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Cell Line
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Cell Lineage / physiology
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism
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Endoribonucleases / genetics
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Endoribonucleases / metabolism
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Gene Expression Regulation, Developmental / physiology*
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Growth Disorders / genetics
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Growth Disorders / metabolism
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Homeobox Protein PITX2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Luteinizing Hormone, beta Subunit / biosynthesis
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Luteinizing Hormone, beta Subunit / genetics
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Lymphoid Enhancer-Binding Factor 1 / genetics
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Lymphoid Enhancer-Binding Factor 1 / metabolism*
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Mice
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Mice, Mutant Strains
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Mice, Transgenic
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Pituitary Gland, Anterior / embryology*
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Pituitary Gland, Anterior / growth & development
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Pro-Opiomelanocortin / biosynthesis
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Pro-Opiomelanocortin / genetics
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Prolactin / biosynthesis
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Prolactin / genetics
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Promoter Regions, Genetic / physiology*
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Ribonuclease III
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Thyrotropin, beta Subunit / biosynthesis
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Thyrotropin, beta Subunit / genetics
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Transcription Factor Pit-1 / biosynthesis*
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Transcription Factor Pit-1 / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Homeodomain Proteins
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Lef1 protein, mouse
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Luteinizing Hormone, beta Subunit
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Lymphoid Enhancer-Binding Factor 1
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MicroRNAs
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Pit1 protein, mouse
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Thyrotropin, beta Subunit
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Transcription Factor Pit-1
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Transcription Factors
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Pro-Opiomelanocortin
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Prolactin
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Endoribonucleases
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Dicer1 protein, mouse
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Ribonuclease III
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DEAD-box RNA Helicases