There are thousands of different neuron populations in our cerebral cortex, but in neurodegenerative diseases only a select neuron population show primary vulnerability and undergo progressive degeneration. Corticospinal motor neurons (CSMN) are large pyramidal neurons that are located in layer V of the motor cortex. Their cellular structure is very unique and they function as the "spokes person"of the cerebral cortex for the initiation and modulation of movement. Voluntary movement is the act of a clever and well-informed mind. Therefore CSMN receive information from numerous neurons, including long-distance projection and local circuitry neurons. CSMN's unique ability to integrate and translate this information into one signal towards spinal cord targets sets it apart from other cortical neurons. Therefore its degeneration has severe consequences that lead to various movement disorders. There is a developing need to understand the basis of CSMN degeneration in diseases. However, identification and visualization of CSMN is not easy as they are embedded among thousands of other neuron populations within the cerebral cortex. We recently generated a novel reporter line, the UCHL1-eGFP mice, in which CSMN are genetically labeled in the motor cortex. eGFP expression under the control of UCHL1 promoter is stable, persistent up to P800 in vivo, and is restricted to CSMN in the motor cortex. CSMN identity of eGFP+ neurons in the motor cortex are identified by anatomy, retrograde labeling, molecular marker expression profile and electrophysiological analysis. This reporter line offers many unique advantages;a) we can for the first time visualize CSMN without any need for a retrograde labeling surgery;b) CSMN can be purified by FACS- mediated approaches at different stages in life;c) the cellular and molecular mechanisms that are responsible for CSMN vulnerability and degeneration can be studied in detail and with precision;d) most importantly this novel reporter line can be crossed to various mouse models of movement disorders to investigate the biology of CSMN with respect to disease. In this proposal, our goal is to bring visual clarity to CSMN in various mouse models of motor neuron diseases. We will be crossing UCHL1-eGFP mice with the recently identified mouse models that show potential involvement of upper motor neuron degeneration in disease pathology. Due to time limitations of R21 grant, we will characterize the timing and extent of CSMN degeneration in a limited number of mouse models, such as the Tdp43A315T and Alsin KO mice. The tools we generate and the approach we develop will help generation and characterization of other reporter mouse models, and will improve our efforts of understanding the cellular and molecular mechanisms behind CSMN vulnerability and degeneration.
Visualization and identification of neuron populations that show selective vulnerability among thousands of different neuron populations within the heterogeneous and complex structure of the cerebral cortex have been one of the major limiting factors for our success in bringing effective treatment strategies to neurodegenerative diseases that primarily affect distinct neuron populations. Corticospinal motor neurons (CSMN) show initial vulnerability and progressive degeneration in numerous diseases such as primary lateral sclerosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis, and we recently developed mouse models in which CSMN are genetically labeled. In this proposal, we will generate novel mouse models of motor neuron diseases that have genetically labeled CSMN, and will characterize the timing and extent of CSMN degeneration, in an effort to generate the tools that are required to bring an understanding on the molecular and cellular basis of selective motor neuron degeneration in neurodegenerative diseases.