Roles of Arginase-1 in Neural Cells
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Arginase-1 (ARG1) is an essential urea cycle (UC) enzyme that catalyzes the hydrolysis of arginine, proposed to also be involved in pre- and post-natal development and post-injury regeneration of neural cells. Genetic mutations in fundamental regions of ARG1 may cause ARG1 deficiency (ARG1D), a UC disorder (UCD) that results in partial or complete loss of functional ARG1 expression. ARG1D presents with late onset neurological phenotypes in comparison to other UCDs, that include: intellectual and growth retardation, and initial spastic diplegia with progression into paraplegia. Because of prominent arginase-1 expression in the nervous system (NS) during embryonic and post-natal development, subsequent upregulation post-injury to the NS, and unique neurological phenotypes of ARG1D in comparison to other UCDs, we hypothesized that ARG1 has pivotal neurobiological roles. To investigate this, we crossed nestin-cre and Arg1 loxP-flanked mouse strains, effectively creating neural (n)Arg1 knockout (KO) mice, which should congenitally lack functional arginase-1 expression in neural cells. Cre-loxP recombination of Arg1 was determined by PCR genotyping and characterization of the mouse model included protein and mRNA expression analysis of various tissues to confirm NS specific KO of arginase-1. Subsequently, nArg1 KO mice were compared to control mice for assessment of body weight, blood amino acid levels, and stride gait cycle utilizing DigiGait Imaging Systems during 8 to 26 weeks of age. To assess the role of Arg1 post-injury in neural cells a sciatic nerve crush injury (SNCI) model was used. Functional tests were carried out to assay differences in axon reinnervation by assessing return of lost motor and sensory function of nArg1 KO mice compared to control mice. Results suggest no temporal differences in axon reinnervation post-SNCI based on the rate of return of sensory function. Gait abnormalities reminiscent of those observed in ARG1-deficient patients were absent. Our results suggest that an absence of Arg1 in neural cells does not contribute to the phenotypes of ARG1 deficiency, nor is Arg1 likely to be crucial for post-injury axonal regeneration in this particular model, although return of motor function displayed modest delays compared to control mice.
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