Spatio-Temporal Expression Pattern of Frizzled Receptors after Contusive Spinal Cord Injury in Adult Rats

Abstract

BackgroundWnt proteins are a large family of molecules that are critically involved in multiple central nervous system (CNS) developmental processes. Experimental evidences suggest a role for this family of proteins in many CNS disorders, including spinal cord injury (SCI), which is a major neuropathology owing to its high prevalence and chronic sensorimotor functional sequelae. Interestingly, most Wnt proteins and their inhibitors are expressed in the uninjured spinal cord, and their temporal expression patterns are dramatically altered after injury. However, little is known regarding the expression of their better-known receptors, the Frizzled family, after SCI. Thus, the aim of the present study was to evaluate the expression of Frizzled receptors in the damaged spinal cord.FindingsBased on the evidence that Wnts are expressed in the spinal cord and are transcriptionally regulated by SCI in adulthood, we analysed the spatio-temporal mRNA and protein expression patterns of Frizzled receptors after contusive SCI using quantitative RT-PCR and single and double immunohistochemistry, respectively. Our results show that almost all of the 10 known Frizzled receptors were expressed in specific spatial patterns in the uninjured spinal cords. Moreover, the Frizzled mRNAs and proteins were expressed after SCI, although their expression patterns were altered during the temporal progression of SCI. Finally, analysis of cellular Frizzled 5 expression pattern by double immunohistochemistry showed that, in the uninjured spinal cord, this receptor was expressed in neurons, oligodendrocytes, astrocytes, microglia and NG2+ glial precursors. After injury, Frizzled 5 was not only still expressed in oligodendrocytes, astrocytes and NG2+ glial precursors but also in axons at all evaluated time points. Moreover, Frizzled 5 was expressed in reactive microglia/macrophages from 3 to 14 days post-injury.ConclusionsOur data suggest the involvement of Frizzled receptors in physiological spinal cord function and in the cellular and molecular events that characterise its neuropathology.

Abrogation of -Catenin Signaling in Oligodendrocyte Precursor Cells Reduces Glial Scarring and Promotes Axon Regeneration after CNS Injury

“…To confirm that canonical Wnt signaling increases after SCI (Liu et al, 2008a;Miyashita et al, 2009;Gonzalez et al, 2012), control and KO female mice (6 -8 weeks of age) were induced with tamoxifen for 3 and 2 d later, given moderate (45 kdyn) contusion injuries to the dorsal spinal cord at T10. At 5 d after a moderate contusion injury (5 days post lesion, dpl), the number of axin2ϩ cells in control animals had increased and the cells were present throughout both the gray and white matter ( Fig.…”

“…In contrast, ␤-catenin signaling is necessary for the injury-induced rapid proliferation of OPCs and increasing Wnt3a expression in the uninjured spinal cord is sufficient to initiate proliferation and a reactive response in OPCs. Thus increases in the expression of Wnts and their receptors after SCI (Liu et al, 2008b;Miyashita et al, 2009;Fernández-Martos et al, 2011;Gonzalez et al, 2012) are likely responsible, at least in part, for the rapid proliferation and mobilization of OPCs after injury. Eliminating ␤-catenin-dependent signaling in OPCs had striking and unexpected consequences for the reactions to injury of other glial cells.…”

“…What these features are remains unknown. Multiple members of the Wnt family of developmental morphogens and their receptors are rapidly increased at sites of brain and spinal cord injury (SCI; Liu et al, 2008a;Miyashita et al, 2009;Fernández-Martos et al, 2011;Gonzalez et al, 2012). While mostly known for their role as developmental regulators, Wnts have multiple functions in the adult brain (Inestrosa and Arenas, 2010).…”

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

“…31 By contrast, the only report describing a role of Wnts in mice SCI claimed that Wnts were not expressed in adulthood and that, after hemisection damage, only a few Wnt ligands (Wnt1, Wnt4, and Wnt5a) and receptors (Ryk and Fz1) were reinduced, playing a key role on corticospinal axonal growth inhibition through noncanonical Wnt5a-Ryk activation. 28 In agreement, SCI has been reported to not promote Wnt canonical activation in BATgal transgenic mice.…”

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

“…Wnt expression surrounding the injury site limits axonal plasticity and regeneration of long-distance projections within the dorsal columns [75,76]. Additionally, there is evidence that Wnt receptors are expressed locally in neural and non-neuronal cells within the injured spinal cord; however, the role of Wnt signaling on these cells has not yet been defined [77,78].…”