Dr Anu Sironen

Cilia related mechanisms in sperm development

My main interests are protein transport mechanisms and sperm tail formation. The functionally similar microtubular core structure, the axoneme, of cilia and sperm tails means that compromised ciliary function can be associated with male infertility. Roles of ciliary genes are poorly understood in sperm development and my goal is to amend this lack of knowledge. My previous studies have demonstrated the importance of intra flagellar transport (IFT) in spermiogenesis and current research interests include elucidation of the role of the transition zone (TZ) in developing sperm and interaction between IFT and TZ. Mutations in genes coding for components of the axoneme, IFT and TZ cause wide range of ciliopathies, but their effects on sperm formation are unknown. The research focus is on characterization of these mechanisms in elongating male germ cells and identification of differences between cilia and sperm.

Specific research questions:

What is the role of TZ in sperm?

TZ has been recently shown to be indispensable structure controlling the protein transport to cilia, but its role is not known in sperm. Our project aims to identify the TZ components in elongating and in mature sperm and establish the role of the TZ in sperm development.

What is the relation between IFT and TZ?

The variability of phenotypes in ciliopathies suggests a cell type specific control of ciliary access and possible link between IFT and TZ formation. Using animal models and cell culture assays we are interested to characterize the effect of decreased IFT velocity on TZ formation and malfunction of TZ on IFT.

How do PCD mutations affect male fertility?

Primary Ciliary Dyskinesia (PCD) is caused by motility defects of respiratory tract cilia and manifested by recurrent infections and loss of lung function starting soon after birth. It can be expected that adult male PCD patients have fertility problems, but the associations of specific mutations with sperm quality have not been assessed. We are interested to underline the functional and structural defects caused by specific PCD genotypes in sperm and identify differences between cilia and sperm tail formation. This information will be utilized to inform PCD patients about their fertility status.

Collaborations:

Imperial College London

Royal Brompton Hospital

Hammersmith Hospital

Queen Mary University of London

University of Leeds

University of Turku

Selected publications:

DILLARD KJ, HYTÖNEN MK, FISCHER D, TANHUANPÄÄ K, LEHTI MS, VAINIO-SIUKOLA K, SIRONEN A, ANTTILA M. A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs. PLoS One. 2018 Sep 20;13(9):e0204073
LEHTI MS, HENRIKSSON H, RUMMUKAINEN P, WANG F, UUSITALO-KYLMÄLÄ L, KIVIRANTA R, HEINO TJ, KOTAJA N,SIRONENA. Cilia-related protein SPEF2 regulates osteoblast differentiation. Scientific Reports, 2018 Jan 16;8(1):859.
LEHTI MS, SIRONEN A. Formation and function of sperm tail structures in association with sperm motility defects. Biology of Reproduction, 2017 Oct 1;97(4):522-536.
LEHTI MS, ZHANG FP, KOTAJA N, SIRONEN A. SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation. Development. 2017 Jul 15;144(14):2683-2693.
LEHTI M., KOTAJA N., SIRONEN A. KIF3A is essential for sperm tail formation and manchette function. Mol Cell Endocrinol. 2013 Sep 5;377(1-2):44-55.
SIRONEN A., KOTAJA N., MULHERN H., WYATT T., SISSON J., PAVLIK J., MIILUNIEMI M., FLEMING M., LEE L. Loss of Spef2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia. Biol. Reprod. 2011 Oct;85(4):690-701.