News & Events
Third annual Jungers Center Symposium
Repairing the nervous system: Lessons from flies, fish, and mice
Monday, May 16, 2011
Vey Conference Center, 11th Floor, Doernbecher Children's Hospital, OHSU
9 a.m. - 12:30 p.m.
Featured Speakers
Michael Coleman, Christine Beattie, Aaron DiAntonio, Tony Wyss-Coray
From long-lived axons to a short-lived protein: WldS and Nmnat2.
Michael Coleman
Babraham Institute, Cambridge
Early loss of axons and synapses and axonal transport impairment are common to many neurodegenerative diseases including motor neuron disease but the molecular events that may link them are poorly understood. Axon transection abolishes transport from the soma but addition of a single protein is sufficient to delay the ensuing Wallerian degeneration by tenfold. This ‘slow Wallerian degeneration’ protein (WldS) is an aberrant protein that arose in a healthy mutant mouse and combines sequences from nicotinamide mononucleotide adenylyl-transferase Nmnat1 and ubiquitin ligase Ube4b. Mislocalisation or overexpression of Nmnat1 or Nmnat3 have similar protective effects. In contrast, depletion of an endogenous Nmnat, the labile isoform Nmnat2, causes Wallerian-like degeneration of uninjured neurites in primary culture. WldS prevents this degeneration, probably by compensating for loss of Nmnat2 in an enzyme-dependent manner. However, the Nmnat function that promotes axon survival may not be NAD+ synthesis. Nmnat2 is abundant in the Golgi apparatus but live imaging shows it is also rapidly and bidirectionally transported along neurites. Our data suggest it is targeted to vesicular structures by palmitoylation, where it frequently comigrates with other Golgi-derived proteins but not with mitochondria. In healthy axons, rapid and constant delivery of this essential protein seems to balance its degradation by the ubiquitin proteasome system, maintaining its level above the threshold needed for axon survival. When axonal transport or neuronal metabolism fails, we propose that failure to replace natural turnover of Nmnat2 limits axon survival. Deficiencies in other axonal cargoes take far longer to limit survival when loss of Nmnat2 is prevented, indicating an important therapeutic window for some disorders if this pathway were appropriately targeted. It is essential now to extend these data in vivo and to understand the upstream and downstream events.
Modeling human motoneuron diseases in zebrafish: Approaches and outcomes.
Christine Beattie
Ohio State University, Columbus
A focus of our research is to understand the cause of motoneuron dysfunction and death in human motoneuron diseases. To this end, we have been using zebrafish to analyze fundamental properties of motoneurons in the context of motoneuron diseases. Here we will focus on the motoneuron disease spinal muscular atrophy (SMA) that is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. The actin binding protein plastin 3 has recently been identified as a modifier of SMA in humans. This is interesting because knowledge of genetic modifiers can lend insight into the disease process. To understand the mechanism of plastin 3 in SMA, we have analyzed zebrafish smn mutants and have generated transgenic zebrafish expressing plastin 3 or SMN. We show that plastin 3 protein levels are severely decreased in smn-/- mutants and adding back SMN can restore these levels. We find that plastin 3 RNA and protein stability are unaffected when SMN is decreased pointing to a role for SMN in plastin 3 translational regulation. We had previously shown that in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions (NMJs). Transgenically driving plastin 3 expression just in motoneurons rescues the decrease in SV2 expression at NMJs. To determine whether plastin 3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving plastin 3 transgenically just in motoneurons rescued both of these defects. These data show that plastin 3 protein levels are dependent on SMN and that plastin 3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of SMN. These data indicate that decreases in plastin 3 contribute to the neuromuscular and movement defects seen when SMN is decreased and that aspects of the SMA phenotype are caused by SMN either directly or indirectly affecting actin dynamics.
The axonal injury response: lessons from flies and mice.
Aaron DiAntonio
Washington University, St. Louis
Axonal injury can trigger both regenerative and degenerative responses. These seemingly disparate outcomes may need to be coordinated for an efficient axonal response to injury. Building on our studies of synaptic development in Drosophila, we have identified an important role for the MAPKKK DLK in promoting both axonal regeneration and degeneration following injury. These functions of DLK are conserved from Drosophila to mice, highlighting the evolutionary conservation of the axonal injury response pathways. We are taking advantage of this conservation to identify novel genes promoting axonal degeneration using genetic techniques in the fly.
A novel role for TGF-beta signaling in adult neurogenesis.
Tony Wyss-Coray
Stanford University
Adult neurogenesis persists in the subventricular and the subgranular zones of the adult mammalian brain. However, the molecular pathways modulating the late events of neurogenesis are poorly understood. We discovered that transforming growth factor-β (TGF-β) signaling is activated in immature and mature neurons of the normal, and more pronounced, of the injured dentate gyrus. Conditional activation of TGF-β signaling in forebrain neurons by constitutively activating TGF-β type I receptor led to an increase in the total number of newborn neurons and resulted in extended migration of immature neurons into the granule cell layer. Newborn neurons with increased TGF-β signaling exhibited enhanced dendritic arborization and accelerated neuronal integration. We conclude that neuronal TGF-β signaling is a potent regulator of maturation and integration of newborn neurons during hippocampal neurogenesis.
