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Mice lacking microRNAs in Pax8-expressing cells develop hypothyroidism and end-stage renal failure.

Bartram MP, Amendola E, Benzing T, Schermer B, de Vita G, Müller RU - BMC Mol. Biol. (2016)

Bottom Line: The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm.Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals.These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model.

View Article: PubMed Central - PubMed

Affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

ABSTRACT

Background: Non-coding RNAs have gained increasing attention during the last decade. The first large group of non-coding RNAs to be characterized systematically starting at the beginning of the 21st century were small oligonucleotides--the so-called microRNAs (miRNAs). By now we have learnt that microRNAs are indispensable for most biological processes including organogenesis and maintenance of organ structure and function. The role of microRNAs has been studied extensively in the development of a number of organs, so far most studies focussed on e.g. the heart or the brain whilst the role of microRNAs in the development and maintenance of complex epithelial organs is less well understood. Furthermore most analyses regarding microRNA function in epithelial organs employed conditional knockout mouse models of the RNAse III Dicer to abrogate microRNA biogenesis. However, there is increasing evidence for Dicer to have multiple functions independent from microRNA maturation. Therefore Dicer independent models are needed to gain further insight into the complex biology of miRNA dependent processes.

Results: Here we analyze the contribution of microRNA-dependent transcriptional control in Pax8-expressing epithelial cells. Pax8 is a transcription factor that is crucial to the development of epithelial organs. The miRNA machinery was disrupted by crossing conditional DiGeorge syndrome critical region 8 (Dgcr8) fl/fl mice to Pax8Cre mice. The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm. Dgcr8 fl/fl; Pax8Cre+ knockout mice died prematurely, developed massive hypothyroidism and end stage renal disease due to a loss of miRNAs in Pax8 expressing tissue.

Conclusion: Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals. These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model.

No MeSH data available.


Related in: MedlinePlus

Decreased expression of kidney specific miRNAs. Using qPCR the expression of several miRNAs was analysed. In line with a key role of Dgcr8 in miRNA processing, the kidney epithelial cell enriched miRNAs miR-192, miR-200b and miR-204 are strongly downregulated. SnoRNA-135 served as endogenous control (n = 4 per group, error bars = SEM, *p < 0.05, **p < 0.01, ***p < 0.001, age of the mice 4–8 weeks)
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Fig5: Decreased expression of kidney specific miRNAs. Using qPCR the expression of several miRNAs was analysed. In line with a key role of Dgcr8 in miRNA processing, the kidney epithelial cell enriched miRNAs miR-192, miR-200b and miR-204 are strongly downregulated. SnoRNA-135 served as endogenous control (n = 4 per group, error bars = SEM, *p < 0.05, **p < 0.01, ***p < 0.001, age of the mice 4–8 weeks)

Mentions: Since Dgcr8 is one of the key components of efficent miRNA biogenesis we analysed the abundance of several miRNAs that have been reported to be enriched in kidney epithelial cells [16, 17]. The expression of miR-192, miR-200b and miR-204 was significantly decreased in kidneys of Dgcr8 knockout mice (Fig. 5).Fig. 5


Mice lacking microRNAs in Pax8-expressing cells develop hypothyroidism and end-stage renal failure.

Bartram MP, Amendola E, Benzing T, Schermer B, de Vita G, Müller RU - BMC Mol. Biol. (2016)

Decreased expression of kidney specific miRNAs. Using qPCR the expression of several miRNAs was analysed. In line with a key role of Dgcr8 in miRNA processing, the kidney epithelial cell enriched miRNAs miR-192, miR-200b and miR-204 are strongly downregulated. SnoRNA-135 served as endogenous control (n = 4 per group, error bars = SEM, *p < 0.05, **p < 0.01, ***p < 0.001, age of the mice 4–8 weeks)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835897&req=5

Fig5: Decreased expression of kidney specific miRNAs. Using qPCR the expression of several miRNAs was analysed. In line with a key role of Dgcr8 in miRNA processing, the kidney epithelial cell enriched miRNAs miR-192, miR-200b and miR-204 are strongly downregulated. SnoRNA-135 served as endogenous control (n = 4 per group, error bars = SEM, *p < 0.05, **p < 0.01, ***p < 0.001, age of the mice 4–8 weeks)
Mentions: Since Dgcr8 is one of the key components of efficent miRNA biogenesis we analysed the abundance of several miRNAs that have been reported to be enriched in kidney epithelial cells [16, 17]. The expression of miR-192, miR-200b and miR-204 was significantly decreased in kidneys of Dgcr8 knockout mice (Fig. 5).Fig. 5

Bottom Line: The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm.Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals.These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model.

View Article: PubMed Central - PubMed

Affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

ABSTRACT

Background: Non-coding RNAs have gained increasing attention during the last decade. The first large group of non-coding RNAs to be characterized systematically starting at the beginning of the 21st century were small oligonucleotides--the so-called microRNAs (miRNAs). By now we have learnt that microRNAs are indispensable for most biological processes including organogenesis and maintenance of organ structure and function. The role of microRNAs has been studied extensively in the development of a number of organs, so far most studies focussed on e.g. the heart or the brain whilst the role of microRNAs in the development and maintenance of complex epithelial organs is less well understood. Furthermore most analyses regarding microRNA function in epithelial organs employed conditional knockout mouse models of the RNAse III Dicer to abrogate microRNA biogenesis. However, there is increasing evidence for Dicer to have multiple functions independent from microRNA maturation. Therefore Dicer independent models are needed to gain further insight into the complex biology of miRNA dependent processes.

Results: Here we analyze the contribution of microRNA-dependent transcriptional control in Pax8-expressing epithelial cells. Pax8 is a transcription factor that is crucial to the development of epithelial organs. The miRNA machinery was disrupted by crossing conditional DiGeorge syndrome critical region 8 (Dgcr8) fl/fl mice to Pax8Cre mice. The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm. Dgcr8 fl/fl; Pax8Cre+ knockout mice died prematurely, developed massive hypothyroidism and end stage renal disease due to a loss of miRNAs in Pax8 expressing tissue.

Conclusion: Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals. These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model.

No MeSH data available.


Related in: MedlinePlus