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Transcriptional control mechanisms in the wall of the urinary bladder. Myocardin family coactivators and the transcriptomic impact of denervation.

Author

Summary, in English

Urological problems can be caused by diseases that affect the bladder wall and its innervation. Contraction and relaxation of smooth muscle cells (SMCs) is essential for maintaining detrusor function and for emptying the bladder. It is well established that a family of regulatory proteins called Myocardin Related Transcription Factors (MRTFs) controls the property of SMCs. SMCs have a number of unique ultrastructural features, including caveolae in the membrane and “dense bodies” in the cytoplasm. An overarching aim of the work presented here was to investigate the regulatory mechanism of the key proteins in caveolae and dense bodies.
The generation of caveolae depends on caveolins and cavins. We found that most caveolae proteins are regulated by MRTFs via proximal promoter sequences. MRTFs thus likely represent major drivers of formation of caveolae in SMCs. We also found that Cavin3 (Prkcdbp) is preferentially expressed in SMCs compared to other cells. Knockout of Cavin3 reduced the number of caveolae in the SMC membrane, but not elsewhere, and at the same time reduced Caveolin-1, Caveolin-3 and Cavin1. This suggests that Cavin3 contributes to the generation of caveolae in SMCs.
Dense bodies in smooth muscle may be regarded as equivalents of Z-discs in striated muscle. The protein Nexilin (NEXN) was previously identified as a Z-disc-localized protein that controls mechanical stability. We found that Nexilin (NEXN) is highly expressed in SMCs and regulated by MRTF- and YAP/TAZ-coactivators. Nexilin was moreover found to be a dense body-associated protein in SMCs that promotes actin polymerization, differentiation and motility.
Bladder wall remodelling in pathological situations is accompanied by reduced innervation. A second aim of this work was to define changes in gene expression after denervation. We show that numerous mRNAs and miRNAs are differentially expressed in the denervated bladder. Pathway analysis indicates that many of the differentially expressed genes are related to proliferation (60%). This is no surprise because the bladder weight increases 5-fold following denervation. Cthrc1 is upregulated at both the mRNA and protein levels, correlating with bladder weight, and overexpression and knockdown of this protein influences SMC proliferation in vitro.
Neural plasticity is influenced by neurotrophic factors released from the target organs. We addressed if the bladder may influence its own nerve supply by such a mechanism. We demonstrate that neurotrophic factors, including NGF, BDNF, and NT-3, are synthesized in the bladder wall, and promote outgrowth of neurites from the pelvic ganglia in vitro, presumably via Trk-receptors.
In conclusion, the studies summarized here provide understanding of the transcriptional control of key proteins and ultrastructural features of SMCs. They also unveil molecular mechanisms of bladder remodelling following denervation. Manipulation of some of the genes identified here represents promising strategies for recovering bladder function in disease.

Publishing year

2018

Language

English

Publication/Series

Lund University, Faculty of Medicine Doctoral Dissertation Series

Volume

2018

Issue

104

Document type

Dissertation

Publisher

Lund University: Faculty of Medicine

Topic

  • Cell and Molecular Biology
  • Urology and Nephrology

Status

Published

Research group

  • Cellular Biomechanics

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-672-4

Defence date

20 September 2018

Defence time

09:00

Defence place

Segerfalksalen, BMC A10, Sölvegatan 17 i Lund