The Megraw lab investigates the functions of centrosomes and cilia in cell division, development and disease. This includes asymmetric division of stem cells, the regulation of centrosomal and other microtubule-organizing centers (MTOCs), metabolic disorders due to loss of centrosome proteins, and regulation of primary cilium assembly and function. We use Drosophila, mouse, and human cell culture models.
Centrosomes perform central roles in cell division, development and disease. They are critical for effective cell division and also for the control of intercellular signaling and environmental sensing through the regulation of primary cilia. Mutations in centriole or centrosome proteins are responsible for an expanding list of human diseases. These include ciliopathies, which impact the structure or function of cilia, and also diseases that impact the control of stem cell proliferation by the centrosome by unknown mechanisms. These pathologies cause autosomal recessive primary microcephaly (MCPH; MIM 251200) and primordial dwarfism syndromes like Seckel syndrome (SCKL, MIM 210600) and microcephalic osteodysplastic primordial dwarfism Majewski type II (MOPD II, MIM 210720) (Megraw et al., 2011).
- The basis of MCPH: a neural stem cell disease.A group of 8 proteins whose genes are mutated in a syndrome called autosomal recessive primary microcephaly (MCPH). Mutations result in severe reduction of the cerebral cortex during embryonic development. We are investigating a new line of evidence that points to the mechanism for this disease.
- Conversion of mitochondria to MTOCs.We discovered an alternative splice product of a centrosome protein that targets to the mitochondria. This protein assembles microtubule-organizing centers on the surface of mitochondria. This is a very novel non-centrosomal MTOC, and represents the first molecular characterization of mitochondrial MTOCs.
- Asymmetric centrosomal control of neural stem cell division.In neural stem cells, we discovered an asymmetric centriole protein that localizes only to the younger mother centriole, and is inherited by the renewed stem cell at each division. This protein regulates stem cell polarity.
- Regulation of centriole duplication.We are investigating a complex of proteins, including centrosomin, that regulate the 'licensing step' that governs centriole duplication during the cell cycle.
- Regulation of cilia assembly.We are investigating the functions of several proteins that are required for proper cilium assembly or function. One new protein we are studying is required for normal locomotion, and affects male mating behavior. Mutants have poor locomotion, frequent seizures, and males appear fertile (have motile sperm), but do not mate with females.