Spatial considerations in neuronal survival signals

NIH RePORTER · NIH · R01 · $545,358 · view on reporter.nih.gov ↗

Abstract

A major, unresolved question in neuroscience is how the highly specialized and distinctive axons that span long-distances are assembled and maintained. We will address these questions as we analyze the Dorsal Root Ganglia (DRG) sensory neurons that enable input of tactile information. These neurons exhibit a distinctive morphology, with a T-shaped axon consisting of a short axon stem that extends from the cell soma, and connects to a very long peripheral process innervating the skin, and to a central process extending into the spinal cord. Both the peripheral and central processes have features characteristic of axons, as the microtubules contain acetylated tubulin and are uniformly oriented with the plus end outwards. This distinctive morphology of sensory neurons enables rapid and unidirectional transmission of tactile information to the central nervous system. The broad goal of work proposed here is to determine how this highly specialized and anatomically distinctive T-shaped axonal structure is assembled and maintained throughout life. In recent studies, my colleagues and I demonstrated that SFPQ, an RNA binding protein, enables axonal localization of several mRNAs critical for maintaining functional axons, and Nerve growth factor (NGF) stimulation regulates SFPQ functions. Our preliminary results suggest a model wherein SFPQ enables coordinated KIF5A-mediated transport of specific mRNA cargos from DRGs to peripheral sensory axons; NGF stimulation dissociates SFPQ from mRNA cargo, initiating translation of proteins essential for maintaining peripheral axons. We propose that SFPQ:mRNA granules are restricted to the peripheral rather than central axons, and that this restriction depends on NGF signaling. Our study plan tests three specific predictions of this model. Taken together, the work proposed here will determine how RNA binding proteins and motor proteins orchestrate morphologic features essential for tactile sensation and will provide new insights into neurologic disorders that cause axonal degeneration and loss of critical sensory abilities.

Key facts

NIH application ID
9904762
Project number
5R01NS050674-13
Recipient
DANA-FARBER CANCER INST
Principal Investigator
ROSALIND A. SEGAL
Activity code
R01
Funding institute
NIH
Fiscal year
2020
Award amount
$545,358
Award type
5
Project period
2005-08-15 → 2022-04-30