Objetivo
The nuclear envelope (NE) harbors key roles in cellular and organismal homeostasis, reflected by a variety of diseases caused by mutations in NE proteins. Despite the fundamental role of the NE in protecting and organizing the genome, still little is known about the molecular mechanisms underlying NE biogenesis, dynamics and functionality. We will address 3 open questions in NE biology, using vertebrate cells as model system. (1) To understand how the functional specification of the NE by transmembrane proteins is generated, we will decipher how membrane proteins are sorted to the inner nuclear membrane (INM). To reach this goal, we will define targeting signals and the mode of NPC passage of INM proteins, and identify the molecular requirements for transport. (2) Based on structural analysis, we will investigate how the molecular organization of LINC complexes, which are formed by interacting pairs of SUN and KASH proteins spanning the NE, determines their role in NE architecture and as tethers of the NE to the cytoskeleton. (3) We will study dynamic changes of the NE that occur at the onset of ’open’ mitosis, when the nuclear compartment is disintegrated to allow for the formation of a cytoplasmic mitotic spindle. NE breakdown (NEBD) presents a dramatic change of cellular architecture and comprises a series of events including disassembly of nuclear pore complexes, the nuclear lamina and retraction of NE membranes into the endoplasmic reticulum. To elucidate the molecular mechanisms controlling and executing these steps of nuclear disassembly, we will characterize the cellular machinery involved in NEBD and unravel the molecular function of identified components. All these questions will be addressed by a blend of in vivo approaches relying on high-end fluorescence imaging linked to computational image analysis, RNAi screening, as well as powerful in vitro systems recapitulating protein transport to the INM or NEBD that we have developed, and biochemical methods.
Ámbito científico
Convocatoria de propuestas
ERC-2012-ADG_20120314
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Régimen de financiación
ERC-AG - ERC Advanced GrantInstitución de acogida
8092 Zuerich
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