Casper Hoogenraad, PhD
Professor
Department of Molecular and Cell Biology
Utrecht University
(March 28, 2017)
Cytoskeleton-Based Mechanisms Underlying the Biology and Diseases of the Nervous System
During brain development, neurons must migrate and form connections. The correct formation of neural circuits depends on multiple factors working together. The movement of axons and dendrites (the parts of the neuron that send and receive messages from other neurons) depend on microtubules. Dr. Hoogenraad discussed his work examining the protein TRIM46. He and his lab have determined that this protein is essential for proper microtubule formation, which, in turn, is essential for normal neural circuit formation. Dr. Hoogenraad also discussed the association of another mutation affecting the protein KBP and alterations in the microtubule and transport of messages. These abnormalities in development may be the basis of certain neurological disorders.
The formation of complex nervous systems requires cytoskeleton-based processes that coordinate proliferation and differentiation of neurons. Neuronal cells undergo major developmental changes as they migrate, develop axons and dendrites, and establish synaptic connections. The structural organization and dynamic remodeling of the neuronal cytoskeleton contribute to all these morphological and functional changes in neurons. Along with the actin cytoskeleton, the assembly, organization, and remodeling of the microtubule cytoskeleton are essential to successfully complete all the different stages of neuronal development. Microtubule-based motor proteins, such as kinesin and dynein, recognize the intrinsic asymmetry of the microtubule lattice and drive cargo transport to either the microtubule plus-end, or minus-end. In various model systems, it has been shown that the microtubule arrays (within axon and dendrites) are highly organized, with respect to their intrinsic polarity, and that this specific microtubule organization is essential to direct polarized cargo transport. In addition, alterations in microtubule organization and cargo trafficking have been described in many neurodegenerative diseases. Thus, while the importance of the microtubule cytoskeleton for proper intracellular trafficking and cargo sorting is unambiguous, how the microtubule in axon and dendrites are organized, and how cargo trafficking is controlled, is largely unknown.
In the first part of the talk, I discussed our efforts to identify the molecular processes that control microtubule organization and dynamics during the different stages of neuronal development. Our recent work indicates that the formation of parallel microtubule bundles in the proximal axon initiates neuronal polarity. We found that the tripartite motif (TRIM) containing protein, TRIM46, plays an instructive role in the initial polarization of neuronal cells. TRIM46 is specifically localized to the newly specified axon and, at later stages, partly overlaps with the axon initial segment (AIS). TRIM46 specifically forms closely spaced parallel microtubule bundles, oriented with their plus-end out. Without TRIM46, all neurites have a dendrite-like mixed microtubule organization resulting in Tau missorting and altered cargo trafficking. By forming uniform microtubule bundles in the axon, TRIM46 is required for neuronal polarity and axon specification in vitro and in vivo. Our data support a model in which TRIM46 defines a unique axonal cytoskeletal compartment for regulating microtubule organization during the early stages of neuronal development.
In the second part of the talk, I discussed a new regulatory mechanism for microtubule-based cargo transport. Previous studies showed homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly and axonal neuropathy. We found that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the microtubule cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A. We found that KBP inhibits KIF1A-mediated synaptic vesicle transport in cultured hippocampal neurons and C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. Our data indicates that KBP functions as a specific kinesin inhibitor that modulates synaptic cargo motility. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients.