Project area A – Testis function and sperm production
A01 Epigenetic mechanisms in the physiological development and malignant transformation of primordial germ cells
Mismigration and accompanying transformation of primordial germ cells during embryo development can lead to infertility and rhabdoid tumours. These tumours are associated with mutations in the SMARCB1 gene, resulting in epigenetic dysregulation. This project gains insights into the genetic mechanisms underlying the transformation of germ cells. Using comprehensive gene-knockout analyses in in vitro models, the relevance of particular genes for the function of germ-cell development will be assessed. This will shed light on the pathomechanisms of male infertility and may be translated into treatment strategies for children with rhabdoid tumours.
Principal investigator
Kornelius Kerl, Prof. Dr. med.
Department of Paediatric Haematology and OncologyA02 Biochemical properties of the seminiferous tubule extracellular matrix
The seminiferous tubules of the testes are ensheathed by a basement membrane interacting with the undifferentiated germ cells nurtured by somatic Sertoli cells. This project studies the role of the basement membrane in the formation of seminiferous tubules. The interplay of Sertoli cells, peritubular myoid cells, and primordial germ cell-like cells as well as the impact of basement-membrane composition and rigidity will be analysed in vitro, using video-imaging and molecular profiling at the RNA and protein level. The generated organoid systems allow for in vitro functional screening of candidate genes in male infertility.
Principal investigators
Johannes Eble, Prof. Dr. rer. nat.
Institute of Physiological Chemistry and Pathobiochemistry
Stefan Schlatt, Prof. Dr. rer. nat.
Centre of Reproductive Medicine and Andrology
A03 Functional genetics in male congenital malformations
The risk for infertility and testicular cancer is significantly increased in males with faulty testicular decent (termed cryptorchidism), which is controlled by testosterone released by testicular Leydig cells. To unravel the mechanisms underlying this common male congenital malformation, this project combines clinical and genetic data. Functional genomics will be applied to assess the impact of candidate genes and testosterone level-associated variants identified in affected patients. In vitro screening approaches will be used to test the function of candidate genes in Leydig cells. This will improve diagnostics and targeted interventions for affected individuals.
Principal investigators
Michael Ziller, Prof. Dr. rer. nat.
Department of Mental Health
Alexander Busch, PD, Dr. med., PhD
Department of General Paediatrics
A04 Testis channelopathies
The most severe form of male infertility is characterised by the absence of germ cells from the seminiferous tubules (Sertoli cell-only, SCO). This phenotype can be caused by loss-of-function variants in the ion channel-encoding gene CLCN2. The aim of this project is to gain mechanistic insights into the role of CLC-2 channels in male infertility. To this end, molecular, cellular, and system functions will be analysed using human iPSC-derived cultures and genetically modified mice. Analyses will include electrophysiology, live-cell imaging as well as in silico modelling, shedding light on the role of ion channels in male infertility.
Principal investigators
Guiscard Seebohm, Prof. Dr. pil. nat.
Institute for Genetics of Heart Diseases, Cellular Electrophysiology and Molecular Biology
Marc Spehr, Prof. Dr. rer. nat.
Institute of Biology II / Department Chemosensation, RWTH Aachen
A05 Spatial sensing of spermatogonial stem cells: cues for cell (dys)function
Men with only few sperm in their ejaculate (cryptozoospermia) feature a mix of seminiferous tubules with normal and impaired germ cell differentiation, which may be caused by mechanical forces acting on the tissue. This project aims to delineate the mechanobiology of the seminiferous tubules and its role in germ cell differentiation. Thus, the mechanical properties of seminiferous tubules with normal versus impaired germ cell differentiation will be determined by atomic force microscopy, combined with spatially resolved transcriptional profiling of enclosed cells. This will reveal how mechanical forces affect germ cell differentiation in tissues from infertile men.
Principal investigators
Nina Neuhaus, Prof. Dr. rer. nat.
Centre of Reproductive Medicine and Andrology
Sara A. Wickström, Prof. MD/PhD
Max Planck Institute for Molecular Biomedicine
A06 Characterisation of the zygotene cilium in human spermatogenesis
Azoospermia, i.e., the lack of sperm in the ejaculate, is often caused by sperm production arrested at meiosis. Studies in zebrafish and mice indicate that meiosis is regulated by a non-motile primary cilium emanating from zygotene spermatocytes. This suggests that ciliopathies, so far rather known to affect sperm motility, may also impact meiosis and spermatogenesis. This project will investigate the role of primary cilia and associated genes and proteins in the human testis, unravelling whether dysfunction of primary cilia represents an as yet unrecognised pathomechanism of human male infertility.
Principal investigators
Corinna Friedrich, PD Dr. rer. nat.
Institute of Reproductive Genetics, Centre of Medical Genetics
Julia Wallmeier, Dr. med.
Department of General Paediatrics
A07 The genomic landscape of non-obstructive azoospermia
Although many azoospermia-related genes have been identified in recent years, most affected men still remain without a causal diagnosis, precluding personalised treatment. The molecular mechanisms underlying azoospermia will, therefore, be elucidated. To this end, the significance of NXT2-interacting proteins as well as the novel X-linked candidate genes TKTL1 and KIAA1210 in male infertility will be explored. Further, the MERGE cohort will be expanded and novel in silico approaches will be employed to identify additional candidate genes for follow up. The results will be translated back into clinical practice to improve care for men with infertility.
Principal investigator