Cell Biology of Centrosomes and Cilia
The Megraw lab investigates the functions of centrosomes and cilia in cell division, development and disease using Drosophila, mouse, and human cell culture models. 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.
Centrosome-based disorders that impact stem cell function and brain development are a major focus of our research.
• The basis of MCPH: a neural stem cell disease
We are investigating a group of 13 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.
• Metabolic control
We are investigating a novel function for centrosome proteins in the control of metabolism. The metabolic regulation controlled by centrosome proteins is essential for neuronal function and survival, especially in the face of particular stresses.
• Asymmetric centrosomal control of neural stem cell division
In neural stem cells, we discovered an asymmetric centriole protein that localizes only to the younger daughter centrosome, and is inherited by the renewed stem cell at each division. This protein regulates stem cell polarity.
• 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.
• 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, Rootletin, 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. Rootletin controls assembly of the rootlet, a cytoskeletal structure, in sensory neurons and is required for all sensory functions.