We have shown that the ER adopts a beautiful ladder structure in the axons of cortical and hippocampal neurons during their development. The key feature of the ladder are rungs where ER tubules intercalate tightly around the microtubules (MT) bundle. Our hypothesis is that ER rungs stabilize the MT bundle during periods of axon growth, like during development or regeneration. We have identified a key factor, Reticulon 2 (Rtn2), that is required for ER ladder structure. We have shown that expression of a mutant form of Rtn2 found in Hereditary Spastic Paraplegia (HSP) patients disrupts ER ladder structure during development and disrupts the trafficking of associated organelles. We are studying the following questions in neurons:

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• How are the key features of the ER ladder generated?
   

• Does the ER ladder play a role in stabilizing the MT bundle during development and during axonal regeneration?
   

• Do other HSP disease mutations that occur in other membrane shaping proteins also disrupt ER ladder structure and axonal growth?
   

• What role do ER tubules play in regulating trafficking, fission, and fusion of associated organelles at contact sites in the axon and growth cone?