The proposed research is important for understanding how nerves grow and branch. In particular, the project focuses on microtubules, which are elongated polymers that provide architecture for the nerve and also act as railways to move proteins and structures down the nerve. For the nerve to grow and branch, there must be mobility within the microtubule array itself. Notably, it has been discovered in recent years that only the shortest microtubules in the nerves are mobile. To generate more mobility within the microtubule array, nerves use special proteins that cut long microtubules into short ones. The purpose of this project is to study how these microtubule "cutters" work, and how they are controlled to get their job done properly. The cutting of microtubules is also important for many other types of cells, so the studies will be of interest and importance across various fields of biology. The general approach will be to make cultures of rat neurons, and then use reliable methods to alter the microtubule cutting proteins, and then see what the effects are on microtubules and the shape of the nerves. The results are expected to show what other molecules and mechanisms the neuron uses to control the cutting proteins so they cut microtubules at the right time and place in the nerves. Broad impact will be achieved through strong efforts to recruit minority students into the graduate program at Drexel University. Even broader impact will be achieved by an outreach to scientists and students in the developing nations of Africa. The Principal Investigator will work with African partners to develop strategies for bringing African students to the USA for part of their training so that the students can prosper, upon their return to their home countries.
Federal Award ID: 0841245 P.I.: Peter W. Baas, Professor of Neurobiology and Anatomy, Drexel University College of Medicine Scientific Progress Neurons are the principal cell type that make up the nervous system. They are remarkable cells, in terms of their highly exaggerated morphology and the intimate relationship between the duties they perform and their unique shapes. A typical vertebrate neuron extends a single elongated axon that has the capacity to grow to virtually unlimted lenghts, or in reality, to reach its appropriate target in the body. Dendrites are multiple in number and are short stout processes. Axons send messages and dendrites recieve messages. Inside the neuron are structural elements called microtubules - these are polymers of the protein tubulin and they provide the architecture for neurons to be able to extend and maintain axons and dendrites. In order to become organized into appropriate patterns in different regions of the neuron, microtubules employ a mechanism called "cut and run," in which longer microtubules are cut into short pieces. The longer microtubules are stationary and provide the backbone for maintaining the structure of the neuron. The short microtubules are highly mobile and can be reconfigured by molecular motor proteins, which are enzymes that generate forces in the microtubules. In this four year NSF grant, efforts were focused on understanding how "cut and run" specficially organizes microtubules in growing axons. The scientific team focused on katanin and spastin, the two most widely recognized microtubule-severing proteins. Much of the work focused on how axons form branches, a process that requires the local severiong of microtubules where new branches are about to form. It was found that katanin and spastin each have their own modes for assisting in branch formation. Spastin accumulates at branch points, whereas katanin does not. Rather, katanin is allowed to sever microtubules locally through the release of a protein called tau from the microtubules in that region. Tau is like a gatekeeper for katanin. In other studies, the team found that the microtubules themselves can be modified to enable them to be better accessible by katanin. For tau, the modification is called phosphorylation. For the microtubules, the modification is called acetylation. The authors also made progress studying how microtubules may be abnormally severed in traumatic brain injury and in diseases such as Alzheimer's disease and Hereditary Spastic Paraplegia. In the final year of the grant funding, they started working on other microtubule-severing proteins, namedly fidgetin and fidgetin-like-2. Broader Impacts The P.I. is the Director of the Graduate Program in Neurosciences at Drexel University and is committed to enhancing diversity in the student body. He has continued his global activities, helping partners in Africa and also teaching in workshops in Uruguay, India and China. This past year, the new class of graduate students consists of roughly half of the class being Under-represented minority students. This includes 2 African-Americans and 3 hispanics. A graduate student in the P.I.'s lab, a highly unique student who started PhD studies at age 16, earned an NSF GRFP. There is no greater priority to the P.I. than the educational mission, which includes both international outreach and diveristy within our own country. He continues to refine the admissions and training process in the graduate program to enhance these goals.
