The nuclear and cytoplasmic compartments of eukaryotic cells are spatially separated by the nuclear envelope, which is composed of a double-layered nuclear membrane, the nuclear lamina and nuclear pore complexes (NPCs). NPCs mediate all molecular exchange between the nucleus and the cytoplasm of interphase cells and they are composed of about 30 different proteins, called nucleoporins. NPCs, and more specifically individual nucleoporins have furthermore roles in other cellular processes, such as  the regulation of gene expression, DNA repair and the cell cycle, all of which, as nucleocytoplasmic transport, of outmost importance for normal cellular function. Defects in nucleocytoplasmic transport as well as dysfunction of nucleoporins have consequently been detected in various human diseases, but the specific roles of nucleoporins in the aetiology of the disease conditions have remained largely elusive. By utilising a combination of imaging techniques, cell biological and biochemical methods as well as genome-editing technologies, we aim to elucidate the molecular mechanisms of human disorders that are related to abnormal function of nucleoporins.    

1.  Elucidating the functional role of nucleoporins Nup98 and Nup214 in (acute myeloid) leukaemia

Acute myeloid leukaemia (AML) is a disease characterised by uncontrolled proliferation of haematopoietic precursor cells often resulting in the disruption of normal haematopoiesis. Impaired differentiation of hematopoietic precursor cells are often associated with chromosomal translocations, which involve fusions of NUP98 to more than 30 different partner genes and of NUP214 to four different partners. Nup98- and Nup214-associated leukaemia are characterised by their aggressiveness and resistance to chemotherapy. Resistance to chemotherapy occurs frequently due to increased self-renewal and/or restored DNA repair pathways and consequently blocked senescence, differentiation and apoptosis. Our intention is to gradually dissect the mechanisms of NUP98- and NUP214-dependent leukemogenesis.

2.  The implication of Nup88 in neuromuscular disorders

Foetal movement is a prerequisite for normal foetal development and growth. Intrauterine movement restrictions cause a broad spectrum of clinically and genetically heterogeneous disorders, referred to as  fetal akinesia deformation sequence (FADS). Affected babies show congenital malformations related to impaired foetal movement and are typically delivered preterm, either stillborn or accompanied by rapid death after birth. Genes encoding components critical for neuromuscular junction formation and acetylcholine receptor clustering represent a major class of FADS disease genes and more recently mutations in NUP88 were identified in individuals affected by FADS. We aim to understand how Nup88 dysfunction leads to this fatal human disorder.

© Biology of the Nucleus 2019