Item Details

abstract

Programmed cell death is one important component of neurodevelopment that, until recently, was thought to be a passive process based upon the lack of trophic support. There is now data that supports the compartmentalized neuron loss theory where each compartment of a nerve cell has a distinct mechanism of maintenance and death. In axons, the Wlds protein is the most widely studied for its ability to delay Wallerian degeneration. Studies have linked the Nmnat1 portion of the Wlds fusion protein to the majority of its ability to protect axons, but recent work has identified Nmnat2 as the endogenous factor involved in axon maintenance. Our goal is to identify the effects that Nmnat2 has on normal development. In this study, a randomly generated mutant was identified with a full knock-out of the Nmnat2 gene and a grossly distended bladder named Bloated Bladder (Blad). Morphological analysis of the Blad mutants showed systemic effects that are all characteristic of an embryo that is paralyzed in utero. The brain itself appeared normal, but motoneuron and sensory neurons were significantly reduced at embryonic day 18.5 (E18.5). Analysis of NF+ peripheral nerves in the hind limb identified a distal-to-proximal pattern of axonal degeneration. Interestingly, the heterozygote population was indistinguishable from the wild-type animals in this portion of the study, even with a 50-75% reduction in Nmnat2 expression. When taking a closer look at the bladder, the bladder starts to show signs of developmental differences at E15.5 in the Blad mutants, but the bladder wall appears to mature and develop the appropriate neuroreceptors even in the absence of functional innervation. There were some interesting trends of reduced muscle strength and activity in a pilot study comparing heterozygotes to wild littermates, but none of the trends appeared to be progressive, and there were not enough animals to make any definitive deductions. In conclusion, Nmnat2 is involved in peripheral axon maintenance during development.

subject

Aging

Bladder

Embronic development

Nmnat2

Peripheral nerves

contributor

Hicks, Amy (author)

Bishop, Colin E (committee chair)

Andersson, Karl-Erik (committee member)

Tytell, Michael (committee member)

Seeds, Michael (committee member)

Hodges, Steve J (committee member)

date

2013-01-09T09:35:20Z (accessioned)

2013-07-09T08:30:11Z (available)

2012 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2013-07-09 (terms)

identifier

http://hdl.handle.net/10339/37673 (uri)

language

en (iso)

publisher

Wake Forest University

title

THE EFFECTS OF NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASE 2 (NMNAT2) ON MOUSE NERVE AND BLADDER DEVELOPMENT

type

Dissertation