Cell cycle-specific recognition of the cell nucleus as cargo for dynein-dependent transport The cell nucleus is transported and positioned in a cell cycle specific manner, a process that is important for cell cycle control and brain development. Human disease mutations of proteins engaged in the transport of the nucleus cause cancer and severe developmental defects of the brain and spinal muscle, including microcephaly and spinal muscular atrophy, the most common genetic cause of death in infants. Despite the importance of nuclear positioning for brain development, it remains largely elusive how the timely transport of the nucleus is initiated and orchestrated. Furthermore, the responsible motor protein complex is cytoplasmic dynein, which orchestrates a vast number of cellular transport events, including RNA/protein complexes, chromosomes, vesicles, mitochondria and organelles, but general principles how the correct cargo is selected at the correct time, have not been established. Cargo is recognized by dynein adaptor proteins, which also link cargo to the dynein machinery. We plan: 1) To establish a structural basis for recognition of the cell nucleus and other cargoes by dynein adaptors. 2) To establish regulatory mechanisms that modulate cargo selectivity of dynein adaptors. More specifically, we plan to establish how the nucleus is recognized as cargo for transport in G2 phase, which is important for cell cycle control and brain development. Our approach combines x-ray crystallography, biophysical methods and cell biological studies. Dynein recruitment sites at the nuclear envelope are provided by two proteins that are part of the nuclear pore complex. They initiate two pathways that are essential for a fundamental process in brain development that is required for differentiation of these brain progenitor cells. In all cells, dynein recruitment is required for positioning the nucleus respective to the centrosome in initial stages of mitosis, and therefore needed for faithful chromosome segregation. Significance: Understanding how dynein motility and cargo selection is regulated is important as it facilitates a vast number of cellular transport events that are essential for faithful chromosome segregation, signal transmission at synapses in the brain and brain development. Results will establish structural principles for cargo selection by dynein adaptors and regulatory pathways that modulate cargo selectivity, and therefore reveal how complex cellular transport events are orchestrated. We plan to establish how the transport of the nucleus is orchestrated, which is crucial for cell cycle control and brain development. Mutations of proteins of these pathways cause cancer and devastating birth defects, including microcephaly, and spinal muscular atrophy, the most common genetic cause of death in infants. Thus, regulatory mechanisms for these transport events are promising targets to help devise therapies for these devastating neuromuscular and brain development diseases.
We plan to establish how the transport of the nucleus is orchestrated, which is important for normal brain development. Human disease mutations of proteins participating in the transport of the nucleus cause cancer, and severe developmental defects of the brain and spinal muscle, including microcephaly and spinal muscular atrophy, which is the most common genetic cause of death in infants. Results will establish regulatory mechanisms that are promising targets to treat these devastating birth defects.