Abstract
The vertebral column, or spine, provides mechanical support and determines body axis posture and motion. The most common malformation altering spine morphology and function is adolescent idiopathic scoliosis (AIS), a three-dimensional spinal deformity that affects approximately 4% of the population worldwide. Due to AIS genetic heterogenicity and the lack of suitable animal models for its study, the etiology of this condition remains unclear, thus limiting treatment options. We here review current advances in zebrafish phenogenetics concerning AIS-like models and highlight the recently discovered biological processes leading to spine malformations. First, we focus on gene functions and phenotypes controlling critical aspects of postembryonic aspects that prime in spine architecture development and straightening. Second, we summarize how primary cilia assembly and biomechanical stimulus transduction, cerebrospinal fluid components and flow driven by motile cilia have been implicated in the pathogenesis of AIS-like phenotypes. Third, we highlight the inflammatory responses associated with scoliosis. We finally discuss recent innovations and methodologies for morphometrically characterize and analyze the zebrafish spine. Ongoing phenotyping projects are expected to identify novel and unprecedented postembryonic gene functions controlling spine morphology and mutant models of AIS. Importantly, imaging and gene editing technologies are allowing deep phenotyping studies in the zebrafish, opening new experimental paradigms in the morphometric and three-dimensional assessment of spinal malformations. In the future, fully elucidating the phenogenetic underpinnings of AIS etiology in zebrafish and humans will undoubtedly lead to innovative pharmacological treatments against spinal deformities.
Highlights
The vertebral column (VC) or spine is the main feature that defines vertebrate animals
4.3.2 The Link Between Reissner Fiber and Cerebrospinal Fluid Contacting Neurons to Conform a Proprioceptive Organ in the Zebrafish Spinal Cord As stated before, the neuropeptides Urp1 and Urp2 are expressed in cerebrospinal fluid (CSF)-cNs, which are localized in the zebrafish spinal cord (Zhang et al, 2018) (Figure 2A). These molecules are down-regulated in the zmynd10 mutant and other cilia zebrafish mutants (Zhang et al, 2018) and their overexpression can rescue body axis curvature in different cilia mutants. These findings indicate that the cilia-driven CSF flow would be necessary to trigger Urp signaling in CSF-contacting neurons (CSF-cNs) and these molecules induce body straightening in zebrafish embryos
The expression of Urp2 in sspo mutants can be restored by the exposition to adrenaline and noradrenaline (Cantaut-Belarif et al, 2020; Lu et al, 2020), neurotransmitters that are normally attached to the Reissner fiber (RF) (Caprile et al, 2003). These findings indicate that, at least in zebrafish, the maintenance of the spinal right axis requires the cilia motility to promote a correct CSF flow, which in turn is necessary for the RF assembly to transport different signaling molecules along the entire nervous system (Figure 2A)
Summary
The vertebral column (VC) or spine is the main feature that defines vertebrate animals. Scoliosis is the most common deformity of the VC in humans and represents a major public health issue (Lonner et al, 2013) In human patients, this malformation is characterized by a lateral curvature greater than 10° (measured by the Cobb angle on X-ray image) and, in some cases, rotational defects (Negrini et al, 2012). This malformation is characterized by a lateral curvature greater than 10° (measured by the Cobb angle on X-ray image) and, in some cases, rotational defects (Negrini et al, 2012) This pathology develops before birth as a failure in vertebral formation or segmentation (congenital scoliosis), or later during postnatal growth (i.e., neuromuscular or idiopathic). Human genomic resources, coupled with phenogenetic information generated by gene function studies in zebrafish, will reveal novel genotype-phenotype correlations during spinal architecture morphogenesis and maintenance
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