Highly conserved molecular pathways, including Wnt signaling, promote functional recovery from spinal cord injury in lampreys

Abstract

In mammals, spinal cord injury (SCI) leads to dramatic losses in neurons and synaptic connections, and consequently function. Unlike mammals, lampreys are vertebrates that undergo spontaneous regeneration and achieve functional recovery after SCI. Therefore our goal was to determine the complete transcriptional responses that occur after SCI in lampreys and to identify deeply conserved pathways that promote regeneration. We performed RNA-Seq on lamprey spinal cord and brain throughout the course of functional recovery. We describe complex transcriptional responses in the injured spinal cord, and somewhat surprisingly, also in the brain. Transcriptional responses to SCI in lampreys included transcription factor networks that promote peripheral nerve regeneration in mammals such as Atf3 and Jun. Furthermore, a number of highly conserved axon guidance, extracellular matrix, and proliferation genes were also differentially expressed after SCI in lampreys. Strikingly, ~3% of differentially expressed transcripts belonged to the Wnt pathways. These included members of the Wnt and Frizzled gene families, and genes involved in downstream signaling. Pharmacological inhibition of Wnt signaling inhibited functional recovery, confirming a critical role for this pathway. These data indicate that molecular signals present in mammals are also involved in regeneration in lampreys, supporting translational relevance of the model.

Regenerative capacity in the lamprey spinal cord is not altered after a repeated transection

“…The recovery curve was well fit by an exponential process that reached a half maximum (t 1/2 ) at 2.6 ± 0.2 wpi (R 2 = 0.78, n=18 lampreys), which was similar to previous reports (Fig. 1C) (Oliphint et al, 2010; Herman et al, 2018). After spinal re-transection, this same cohort of lampreys recovered to ∼85% of normal swimming movements by 11 wpi, reaching half maximum (t 1/2 ) at 2.4 ± 0.1 wpi (R 2 = 0.78, n=18 lampreys) (Fig.…”

“…After spinal transection or re-transection, the lampreys’ swimming movements were scored twice per week during the recovery periods, as previously described (Oliphint et al, 2010; Herman et al, 2018). The scoring criteria were as follows: 0 – immediately post-operatively, lampreys exhibited no response to a light tail pinch; 1 – only head movements were observed; no tail movements occurred below the lesion site; 2 – brief periods of self-initiated swimming occurred, but with atypical movements and body shapes; 3 – lampreys demonstrated longer periods of swimming with more normal undulations and fewer abnormalities; 4 – lampreys exhibited persistent bouts of swimming with normal sinusoidal undulations that were comparable to uninjured, control lampreys.…”

Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation

“…Previous studies have identified Wnt signaling as a regulator of regeneration in multiple contexts (46)(47)(48)(49), including the retina (50-52). Thus, we examined Wnt signaling to begin to gain mechanistic insight into the molecular mechanisms underlying RPE regeneration.…”

Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK

“…Our findings represent a prime example of how the lamprey genomes can reveal the origins of vertebrate-specific traits (66)(67)(68). The early evolutionary divergence of lampreys from the majority of living vertebrates (69-72) has repeatedly illuminated highly conserved elements of vertebrate molecular biology including basic developmental processes such as how the brain and nerves develop and revealing genes whose activity aids spinal cord healing (73).…”