Nicotinamide Mononucleotide Adenylyltransferase 2 (Nmnat2) Regulates Axon Integrity in the Mouse Embryo

Abstract

Using transposon-mediated gene-trap mutagenesis, we have generated a novel mouse mutant termed Blad (Bloated Bladder). Homozygous mutant mice die perinatally showing a greatly distended bladder, underdeveloped diaphragm and a reduction in total skeletal muscle mass. Wild type and heterozygote mice appear normal. Using PCR, we identified a transposon insertion site in the first intron of Nmnat2 (Nicotinamide mononucleotide adenyltransferase 2). Nmnat2 is expressed predominantly in the brain and nervous system and has been linked to the survival of axons. Expression of this gene is undetectable in Nmnat2blad/blad mutants. Examination of the brains of E18.5 Nmnat2blad/blad mutant embryos did not reveal any obvious morphological changes. In contrast, E18.5 Nmnat2blad/blad homozygotes showed an approximate 60% reduction of spinal motoneurons in the lumbar region and a more than 80% reduction in the sensory neurons of the dorsal root ganglion (DRG). In addition, facial motoneuron numbers were severely reduced, and there was virtually a complete absence of axons in the hind limb. Our observations suggest that during embryogenesis, Nmnat2 plays an important role in axonal growth or maintenance. It appears that in the absence of Nmnat2, major target organs and tissues (e.g., muscle) are not functionally innervated resulting in perinatal lethality. In addition, neither Nmnat1 nor 3 can compensate for the loss of Nmnat2. Whilst there have been recent suggestions that Nmnat2 may be an endogenous modulator of axon integrity, this work represents the first in vivo study demonstrating that Nmnat2 is involved in axon development or survival in a mammal.

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

“…However, apart from Drosophila Nmnat (Wen et al, 2011;Fang et al, 2012), currently only mouse Nmnat2 has an endogenous role in promoting axonal stability Hicks et al, 2012). It is important to note, beyond their neuronal roles, Nmnats also have obligate roles in NAD + metabolism and multiple cellular processes across species (Zhai et al, 2009;Lin et al, 2010).…”

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

“…NAD is an essential co-enzyme for several biological process, such as cell death, energy metabolism and calcium mobilization. NMNAT2 is highly expressed in the brain, and along with axon protection following injury (44)(45)(46)(47)(48)(49) is implicated in neurodegenerative disease (50)(51)(52)(53). While functional genetics indicate PHR proteins can inhibit NMNAT2, the biochemical mechanism by which this occurs remains untested.…”

Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

“…Several articles have suggested the implication of Nmnat2 in axonal cell survival and protection (22,23). Nmnat1 and Nmnat2 also have essential roles in axonal growth and survival during embryogenesis as their deficiency in mice results in embryonic lethal (21,24,25).…”