Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology

Abstract

The spine provides structure and support to the body, yet how it develops its characteristic morphology as the organism grows is little understood. This is underscored by the commonality of conditions in which the spine curves abnormally such as scoliosis, kyphosis and lordosis. Understanding the origin of such spinal curves has been challenging in part due to the lack of appropriate animal models. Recently, zebrafish have emerged as promising tools with which to understand the origin of spinal curves. Using zebrafish, we demonstrate that the Urotensin II-related peptides (URPs), Urp1 and Urp2, are essential for maintaining spine morphology. Urp1 and Urp2 are 10-amino acid cyclic peptides expressed by neurons lining the central canal of the spinal cord. Upon combined genetic loss of Urp1 and Urp2, adolescent-onset planar curves manifested in the caudal region of the spine. Highly similar curves were caused by mutation of Uts2r3, an URP receptor. Quantitative comparisons revealed that Urotensin-associated curves were distinct from other zebrafish spinal curve mutants in curve position and direction. Last, we found that the Reissner fiber, a proteinaceous thread that sits in the central canal and has been implicated in the control of spine morphology, breaks down prior to curve formation mutants with perturbed cilia motility but was unaffected by loss of Uts2r3. This suggests a Reissner fiber-independent mechanism of curvature in Urotensin-deficient mutants. Overall, our results show that Urp1 and Urp2 control zebrafish spine morphology and establish new animal models of spine deformity.

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

“…We found that 106 out of 614 upregulated genes were targets of Foxj1, among which 77 were direct targets (Supplementary Table 3). Several genes encoding regulators of embryonic axis curvature were also upregulated in rpgrip1l -/- fish, among which pkd1b (37), urp1 and urp2 (12,13,16) and sspo (5,10,11). Finally, GO terms enrichment analysis also highlighted processes associated with inflammation and innate and adaptive immune responses, as described for the scoliotic ptk7 model (19) sharing for example irg1l and complement genes up-regulation (Fig 5 C, E, and Supplementary fig 4A).…”

Loss of CSF-contacting neuron sensory function is associated with a hyper-kyphosis of the spine reminiscent of Scheuermann’s disease

“…In zebrafish, CSF-cNs are also involved in spine deformities reminiscent of AIS, which rely on the maintenance of a controlled expression level of Urp1 and Urp2, two neuropeptides expressed from the embryonic life to adulthood in these sensory neurons 33 . Indeed, urp1;urp2 double mutants were recently reported to develop AIS-like phenotypes is zebrafish 51 , 52 . Moreover, a downregulation of Urp1/2 peptides expression level was reported in AIS mutant models with defective Reissner fiber acting upstream of CSF-cNs 18 , 19 .…”

Piezo1 Mutant Zebrafish as a Model of Idiopathic Scoliosis

“…As shown in Figure 3A, the vertebrae were generally curved, but there were no significant changes in the shape of the neural or haemal arches. To assess the deformity of individual vertebrae causing the curvature, the size of individual vertebrae was measured and expressed as the ratio of anterior/posterior height (H1/H2) and dorsal/ventral length (L1/L2) (Bearce et al, 2022). Figure 4 shows data for the 8th to 13th vertebrae of 5 individual fish.…”