RNA-Seq analysis after spinal cord injury in lamprey reveals distinct transcriptional responses during functional recovery in spinal cord and brain

The lamprey is a vertebrate that, unlike mammals, achieves spontaneous recovery after spinal cord transection. Despite anatomical, physiological, and behavioral data on spinal cord regeneration in lamprey, the molecular mechanisms underlying this capacity are largely unknown. To address this, we used RNA-Seq to obtain transcriptional profiles from uninjured animals and at 10 time points ranging from 6 hours to 12 weeks post injury. Overall, 4208 (spinal cord) and 3788 (brain) transcripts are differentially expressed (DE). Complex intraspinal and supraspinal responses were induced acutely and occurred even at chronic phases of recovery. Leveraging functional data for mammalian homologs of DE genes (via Enrichr) permitted identification of enriched conserved genes and pathways. These included genes and pathways induced after mammalian peripheral nerve injury, such as those associated with regeneration, immune function, cell growth, proliferation and cell death. For example, ATF3, a transcription factor implicated in mammalian peripheral nerve regeneration, is highly expressed and enriched in lamprey spinal cord and brain after SCI. Other homologs of regeneration-associated genes that are differentially expressed after SCI include members of the WNT, HDAC, SOX, SMAD, KLF, and JUN families. This study provides the first comprehensive view of transcriptional responses during successful anatomical and functional recovery from spinal cord injury in lamprey, and reveals unexpectedly large changes in transcription in the brain, which is quite distant from the spinal lesion site. Gene expression patterns associated with functional recovery in lamprey may be useful in guiding studies aimed at modulating mammalian responses to SCI.