TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance

Abstract

Complex nervous systems achieve proper connectivity during development and must maintain these connections throughout life. The processes of axon and synaptic maintenance and axon degeneration after injury are jointly controlled by a number of proteins within neurons, including ubiquitin ligases and mitogen activated protein kinases. However, our understanding of these molecular cascades is incomplete. Here we describe the phenotype resulting from mutation of TMEM184b, a protein identified in a screen for axon degeneration mediators. TMEM184b is highly expressed in the mouse nervous system and is found in recycling endosomes in neuronal cell bodies and axons. Disruption of TMEM184b expression results in prolonged maintenance of peripheral axons following nerve injury, demonstrating a role for TMEM184b in axon degeneration. In contrast to this protective phenotype in axons, uninjured mutant mice have anatomical and functional impairments in the peripheral nervous system. Loss of TMEM184b causes swellings at neuromuscular junctions that become more numerous with age, demonstrating that TMEM184b is critical for the maintenance of synaptic architecture. These swellings contain abnormal multivesicular structures similar to those seen in patients with neurodegenerative disorders. Mutant animals also show abnormal sensory terminal morphology. TMEM184b mutant animals are deficient on the inverted screen test, illustrating a role for TMEM184b in sensory-motor function. Overall, we have identified an important function for TMEM184b in peripheral nerve terminal structure, function, and the axon degeneration pathway.

TMEM184b is necessary for IL-31 induced itch

“…Supporting this idea, Tlx3 nociceptor-specific knockouts show loss of pruriceptive populations, and pruriceptive markers showing reduced expression in Tlx3 mutant DRGs significantly overlap with Tmem184b-affected genes (Huang et al, 2017;Lopes et al, 2012). Intriguingly, the effect of blockade of Wnt secretion on the morphology of the mouse neuromuscular junction is strikingly similar to that seen in Tmem184b-mutant mice, further implicating a link between Tmem184b and Wnt signaling (Bhattacharya et al, 2016;Shen et al, 2018). Future experiments should test how Tmem184b activity and appropriate Wnt signaling in early sensory development are associated.…”

“…Tmem184b is required for efficient axon degeneration following nerve injury, and also for proper sensory and motor nerve terminal maintenance (Bhattacharya et al, 2016). In mice lacking Tmem184b, nociceptive terminals in the epidermis show swollen endings, and mice show deficits in broad measures of sensorimotor behavior (Bhattacharya et al, 2016). Here we show that Tmem184b controls the expression of a large cohort of sensory receptors in the DRG, specifically those in the NP3/C2 population mediating pruriception.…”

“…Tmem184b gene-trap mice have been described previously. (Bhattacharya et al, 2016) Mice were bred to Sst Cre and Rosa-Flox-stop-Flox-tdTomato (also called Ai9) (lines 013044 and 007909, Jackson Laboratory, Bar Harbor, ME) for histological quantification of the C2 population. Only heterozygous Sst Cre mice were used for experiments due to the possible disruption of normal somatostatin expression in homozygous Cre mice.…”

“…Transmembrane protein 184b (Tmem184b) is a relatively uncharacterized member of the Transporter-Opsin-GPCR (TOG) superfamily of proteins (Yee et al, 2013). Tmem184b is required for efficient axon degeneration following nerve injury, and also for proper sensory and motor nerve terminal maintenance (Bhattacharya et al, 2016). In mice lacking Tmem184b, nociceptive terminals in the epidermis show swollen endings, and mice show deficits in broad measures of sensorimotor behavior (Bhattacharya et al, 2016).…”

Vacuolar protein sorting 4 is required for silkworm metamorphosis

“…MVB proteins have been shown to regulate the development and function of the nervous system in the mouse and fruit fly (Bhattacharya et al, 2016;Bulgari et al, 2018) and the reproductive system in the fruit fly and human (Corrigan et al, 2014;Pocognoni et al, 2015). They also function in various stages of embryogenesis in the mouse and fruit fly (Shim et al, 2006;Eikenes et al, 2015;Morawa et al, 2015).…”