ukb.uni-bonn.de

Department of Biophysical Imaging

Primary ciliary signaling and function

Primary cilia are considered as sensory organelles that receive extracellular signals from the environment and transduce this information into a cellular response. Cyclic-nucleotide signaling has been proposed to be an evolutionary conserved signaling pathway, which acts not only in specialized sensory cilia but also in other cilia. Whereas in motile cilia or flagella, e.g. of Paramecium, Chlamydomonas, airway epithelial cells, or mammalian sperm, cAMP regulates ciliary beating, the role of cAMP signaling in non-motile primary cilia is much less understood. Ciliary G-protein coupled receptors (GPCRs) are believed to act as extrasynaptic signaling devices, which sense the local environment. Upon stimulation, ciliary GPCRs have been proposed to locally change the cAMP concentration in the primary cilium, thereby, controlling cellular functions like gene expression. However, the cellular responses downstream of ciliary cAMP signaling and the physiological functions are rather enigmatic. We apply an interdisciplinary approach combining optogenetics, genetically-encoded biosensors, high-resolution imaging, cell biology, systems biology, and biochemistry to answer a fundamental biological question - what is the physiological function of primary cilia.  

 

Sperm signaling and function

Fertilization is exceptionally complex and, depending on the species, happens in entirely different environments. Various chemical and physical cues guide sperm to the egg. To cope with the panoply of challenges to reach and fertilize the egg, sperm from different species have developed their own unique repertoire of signaling molecules and mechanisms. We investigate sperm signaling and function in mammals, in particular in mice. We have developed a number of different knockout and transgenic mouse models to study sperm signaling in vitro and in vivo.

 

 

Glycosphingolipid function in health and disease

The homeostasis of the glycosphingolipid GlcCer plays an important role for motile cilia function. GlcCer is synthesized from glucose and ceramide by a glucosyl transferase, and metabolized by the beta-glucosidases GBA1 and GBA2.  GBA1 is a lysosomal enzyme, which is active at acidic pH, whereas GBA2 is localized at the cytosolic site of the ER and Golgi with a pH optimum at pH 6. Loss-of-function mutations in GBA1 in human patients result in lysosomal GlcCer accumulation, causing the life-threatening lysosomal storage disorder Gaucher disease. Mutations in the GBA2 gene have been associated with locomotor dysfunction in ataxia patients. However, the main phenotype of GBA2 knockout-mice is male infertility due to a severe sperm morphological defect called globozoospermia: the sperm head is round rather than sickle-shaped, the acrosome, which is needed to penetrate the egg for fertilization, is not formed properly, and sperm motility is impaired. Both, motile and primary cilia constitute a unique microdomain, containing not only a certain protein repertoire and organization, but also forming a distinct membrane domain, whose lipid composition is different from the cell body. How glycosphingolipids contribute to this microdomain architecture is not well understood. We study the role of lipids in controlling ciliary signaling using high-resolution imaging, cell biology, systems biology, and biochemistry.

 

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