Regulating Wnt signaling: a strategy to prevent neurodegeneration and induce regeneration.

During the past three decades, Wingless/Int (Wnt) signaling has emerged as an essential regulator crucial for neuronal development and maintenance (Inestrosa and Arenas, 2010). In addition, Wnt signaling was recently shown to be involved in the regulation of synaptic function and plasticity, which is critical for learning and memory (Oliva et al., 2013). Deregulation of Wnt signaling has been proposed as a key contributor to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD). This increasing knowledge of the specific roles of Wnt signaling cascades during different stages of life has suggested innovative therapeutic strategies for the treatment of neurodegenerative diseases. The reviews under the theme ‘Wnt Signaling Cascades in Neurodevelopment, Neurodegeneration and Regeneration’ published in this issue of JMCB provide an up-to-date overview of the importance of Wnt signaling in midbrain dopaminergic (mDA) development, synaptic maintenance in the hippocampus, neuroinflammatory responses, development of neurodegenerative diseases, and highlight new therapeutic approaches. The majority of dopamine-synthesizing neurones are located in the ventral midbrain. This cell population is crucial for the control and modulation of motor function, cognition, affect, motivation, and reward behaviours. Degeneration of these neurones leads to the typical extrapyramidal motor dysfunctions seen in individuals with PD. The aetiology of PD is poorly understood but work performed over the last two decades has identified a growing number of genetic defects that underlie this condition. Dr Berwick and Harvey reviewed an increasing body of evidence connecting genes implicated in PD, such as LRRK2 and PARK2, with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanism underlying PD. The involvement of LRRK2 in Wnt signaling is of particular interest, since patients harbouring LRRK2 mutations develop PD symptoms that are indistinguishable from idiopathic PD. Dr Marchetti’s group summarized recent evidence suggesting that PD risk factors associated with increased inflammation (including aging and neurotoxin exposure) antagonize Wnt/b-catenin signaling in dopaminergic neurones and neuronal stem cells in the subventricular zone, which is important for adult neurogenesis. Wnt signaling was further suggested to participate in neuroimmune responses via crosstalk between astrocytes, microglia, neurones, and stem/ neuroprogenitor cells. Supporting evidence showed an inter-dependence of inflammation and Wnt/bcatenin signaling in MPTP-induced loss and subsequent repair of dopaminergic neurones. Pharmacological intervention targeting inflammatory responses prevented b-catenin downregulation and restored neurogenesis (L’Episcopo et al., 2012). This suggests an interaction of Wnt signaling with inflammatory pathways activated following neuronal insults with implications for the pathogenesis and treatment of PD. The review by Dr Joksimovic and Awatramani highlights the importance of b-catenin, a central component of the canonical Wnt/b-catenin signaling cascade, for the specification and differentiation of mesodiencephalic dopaminergic neurones. Wnt/b-catenin signaling was shown to be critical for the neurogenic potential of these neurones that originate from the midbrain floor plate. Conditionalb-catenin ablation in the floor plate, allowing normal early Wnt/b-catenin signaling in the midbrain, altered the function of dopaminergic progenitors, including a reduced expression of key genes such as Lmx1a, Otx2, Msx1, and Ngn2, and a decrease in postmitotic mDA neurones. Interestingly, excessive b-catenin supply to the midbrain floor plate had the opposite effect on gene expression but also resulted in fewer postmitotic mDA. This suggests that a dosage effect of b-catenin is crucial for the fine regulation of canonical Wnt signaling.