Functional Characterisation of Nuclear Morphology

• Applicant: Professor Dr. Jörg Großhans
• Subject Area: Cell Biology
• Term: from 2007 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 39194627

• Final Report Year: 2015

Final Report Abstract

It has been a long-standing observation that changes in nuclear morphology are associated with specific steps in development and differentiation, certain pathologies and ageing. Nuclear morphology is largely determined by the nuclear envelope and the nuclear lamina that is associated with the inner nuclear membrane. Strikingly, mutations in genes encoding components of the nuclear lamina lead to a diverse class of diseases, subsumed as laminopathies. The Hutchinson-Gilfert progeria syndrome, as the most prominent example, is caused by a mutation in the LaminA gene, which in the majority of cases leads to a overexpression of a permanently farnesylated version of the LaminA protein. With our experiments we could show that overexpression of farnesylated proteins of the inner nuclear membrane in adult Drosophila flies induces ageing associated phenotypes, including reduced life span and age-dependent behaviour. By this we established an experimental model for HPGS in Drosophila. As the farnesylated proteins associate with the inner nuclear membrane, we investigated the interaction of farnesylated Kugelkern and Lamin with chemically defined phospholipid membranes in vitro. We found that the association of the farnesylated proteins induces shape changes in the bilayer transforming spherical liposomes into tubes. This indicates an assymmetric interaction with the outer leflet of the bilayer. As tubulation was not induced by generic farnesylated proteins, additional interactions between the C-terminal parts of Kugelkern and Lamins are also involved in membrane interaction. Our studies revealed a new function of Lamins in that the farnesylated C-terminal globular domain of Lamin interacts with the membrane and is able to induce shape changes of the phospholipid bilayer.

Publications

• The farnesylated nuclear proteins Kugelkern and Lamin B promote aging-like phenotypes in Drosophila flies. Aging Cell, 7 (2008) 541-551
  A Brandt, G Krohne, J Großhans
  
• The farnesylated nuclear proteins Kugelkern and LaminDm0 affect nuclear morphology by directly interacting with the nuclear membrane. Mol Biol Cell 21 (2010) 2409-2420
  M Polychronidou, A Hellwig, J Großhans
  
• Determining nuclear shape: the role of farnesylated nuclear proteins. Nucleus 2 (2011) 17-23
  M Polychronidou, J Großhans