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Purpose Scoliosis can be treated with vertebral body tethering (VBT) as a motion-sparing procedure. However, the knowledge of how growth is affected by a tether spanning multiple levels is unclear in the literature. Three-dimensional true spine length (3D-TSL) is a validated assessment technique that accounts for the shape of the spine in both the coronal and sagittal planes. This study aimed to assess if 3D-TSL increases over a five-year period after VBT implantation in thoracic curves for idiopathic scoliosis. Methods Prospectively collected radiographic data from an international pediatric spine registry was analyzed. Complete radiographic data over three visits (post-operative, 2 years, and 5 years) was available for 53 patients who underwent VBT. Results The mean age at instrumentation of this cohort was 12.2 (9–15) years. The average number of vertebrae instrumented was 7.3 (SD 0.7). Maximum Cobb angles were 50° pre-op, which improved to 26° post-op ( p  < 0.001) and was maintained at 5 years (30°; p  = 0.543). Instrumented Cobb angle was 22° at 5 years ( p  < 0.001 vs 5-year maximum Cobb angle). An accentuation was seen in global kyphosis from 29° pre-operative to 41° at 5 years ( p  < 0.05). The global spine length (T1-S1 3D-TSL) started at 40.6 cm; measured 42.8 cm at 2 years; and 44.0 cm at the final visit (all p  < 0.05). At 5 years, patients reached an average T1-S1 length that is comparable to a normal population at maturity. Immediate mean post-operative instrumented 3D-TSL (top of UIV–top of LIV) was 13.8 cm two-year length was 14.3 cm; and five-year length was 14.6 cm (all p  < 0.05). The mean growth of 0.09 cm per instrumented level at 2 years was approximately 50% of normal thoracic growth. Patients who grew more than 0.5 cm at 2 years had a significantly lower BMI (17.0 vs 19.0, p  < 0.05) and smaller pre-operative scoliosis (48° vs 53°, p  < 0.05). Other subgroup analyses were not significant for age, skeletal maturity, Cobb angles or number of spanned vertebras as contributing factors. Conclusions This series demonstrates that 3D-TSL increased significantly over the thoracic instrumented levels after VBT surgery for idiopathic scoliosis. This represented approximately 50% of expected normal thoracic growth over 2 years.

Flexible spine tethering is a relatively novel fusionless surgical technique that aims to correct scoliosis based on growth modulation due to the pressure exerted on the vertebral body epiphyseal growth plate. The correction occurs in two phases: immediate intraoperative and postoperative with growth. The aim of this study was to evaluate the reactivation of vertebral growth plate function after applying corrective forces. The rat tail model was used. Asymmetric compression and distraction of caudal growth plates were performed using a modified external fixation apparatus. Radiological and histopathological data were analysed. After three weeks of correction, the activity of the structures increased across the entire growth plate width, and the plate was thickened. The height of the hypertrophic layer and chondrocytes on the concave side doubled in height. The height of chondrocytes and the cartilage thickness on the concave and central sides after the correction did not differ statistically significantly from the control group. Initiation of the correction of scoliosis in the growing spine, with relief of the pressure on the growth plate, allows the return of the physiological activity of the growth cartilage and restoration of the deformed vertebral body.

Capicua (Cic), a transcriptional repressor frequently mutated in brain cancer oligodendroglioma, is highly expressed in adult neurons. However, its function in the dendritic growth of neurons in the hippocampus remains poorly understood. Here, we confirmed that Cic was expressed in hippocampal neurons during the main period of dendritogenesis, suggesting that Cic has a function in dendrite growth. Loss-of-function and gain-of function assays indicated that Cic plays a central role in the inhibition of dendritic morphogenesis and dendritic spines in vitro . Further studies showed that overexpression of Cic reduced the expression of Ets in HT22 cells, while in vitro knockdown of Cic in hippocampal neurons significantly elevated the expression of Ets. These results suggest that Cic may negatively control dendrite growth through Ets, which was confirmed by ShRNA knockdown of either Etv4 or Etv5 abolishing the phenotype of Cic knockdown in cultured neurons. Taken together, our results suggest that Cic inhibits dendritic morphogenesis and the growth of dendritic spines through Ets.

Integrated in vitro models of human organogenesis are needed to elucidate the multi-systemic events underlying development and disease. Here we report the generation of human trunk-like structures that model the co-morphogenesis, patterning and differentiation of the human spine and spinal cord. We identified differentiation conditions for human pluripotent stem cells favoring the formation of an embryo-like extending antero-posterior (AP) axis. Single-cell and spatial transcriptomics show that somitic and spinal cord differentiation trajectories organize along this axis and can self-assemble into a neural tube surrounded by somites upon extracellular matrix addition. Morphogenesis is coupled with AP patterning mechanisms, which results, at later stages of organogenesis, in in vivo-like arrays of neural subtypes along a neural tube surrounded by spine and muscle progenitors contacted by neuronal projections. This integrated system of trunk development indicates that in vivo-like multi-tissue co-morphogenesis and topographic organization of terminal cell types can be achieved in human organoids, opening windows for the development of more complex models of organogenesis. A patterned neural tube and somites in an embryonic context are generated in vitro.

With over 18,000 species, the Acanthomorpha, or spiny-rayed fishes, form the largest and arguably most diverse radiation of vertebrates. One of the key novelties that contributed to their evolutionary success are the spiny rays in their fins that serve as a defense mechanism. We investigated the patterning mechanisms underlying the differentiation of median fin Anlagen into discrete spiny and soft-rayed domains during the ontogeny of the direct-developing cichlid fish Astatotilapia burtoni. Distinct transcription factor signatures characterize these two fin domains, whereby mutually exclusive expression of hoxa13a/b with alx4a/b and tbx2b marks the spine to soft-ray boundary. The soft-ray domain is established by BMP inhibition via gremlin1b, which synergizes in the posterior fin with shh secreted from a zone of polarizing activity. Modulation of BMP signaling by chemical inhibition or gremlin1b CRISPR/Cas9 knockout induces homeotic transformations of spines into soft rays and vice versa. The expression of spine and soft-ray genes in nonacanthomorph fins indicates that a combination of exaptation and posterior expansion of an ancestral developmental program for the anterior fin margin allowed the evolution of robustly individuated spiny and soft-rayed domains. We propose that a repeated exaptation of such pattern might underly the convergent evolution of anterior spinyfin elements across fishes.

Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Z ptk7 ) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZ ptk7 ) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease. Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.

Purpose This article aims to provide an overview of how spinal deformities can alter normal spine and thoracic cage growth. Methods Some of the data presented in this article are gathered from studies performed in 1980 and 1990, and their applicability to populations of different ethnicity, geography or developmental stage has not yet been elucidated. In the present article, older concepts have been integrated with newer scientific data available to give the reader the basis for a better understanding of both normal and abnormal spine and thoracic cage growth. Results A thorough analysis of different parameters, such as weight, standing and sitting height, body mass index, thoracic perimeter, arm span, T1–S1 spinal segment length, and respiratory function, help the surgeon to choose the best treatment modality. Respiratory problems can develop after a precocious vertebral arthrodesis or as a consequence of pre-existing severe vertebral deformities and can vary in patterns and timing, according to the existing degree of deformity. The varying extent of an experimental arthrodesis also affects differently both growth and thoracopulmonary function. Conclusions Growth is a succession of acceleration and deceleration phases and a perfect knowledge of normal growth parameters is mandatory to understand the pathologic modifications induced on a growing spine by an early onset spinal deformity. The challenges associated with the growing spine for the surgeon include preservation of the thoracic spine, thoracic cage, and lung growth without reducing spinal motion.

Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

Limbs and vertebrae elongate by endochondral ossification, but local growth control is highly modular such that not all bones are the same length. Compared to limbs, which have a different evolutionary and developmental origin, far less is known about how individual vertebrae establish proportion. Using the jerboa and mouse tail skeletons, we find that cell number is a common driver of limb and vertebral proportion in both species. However, chondrocyte hypertrophy, which is a major driver of proportion in all mammal limbs, is limited to the extreme disproportionate growth of jerboa mid-tail vertebrae. The genes associated with differential growth in the vertebral skeleton overlap significantly, but not substantially, with genes associated with limb proportion. Among shared candidates, loss of Natriuretic Peptide Receptor 3 in mice causes disproportionate elongation of the proximal and mid-tail vertebrae, in addition to the proximal limb. Our findings therefore, reveal cellular processes that tune the growth of individual vertebrae while also identifying natriuretic peptide signaling among genetic control mechanisms that shape the entire skeleton. Vertebra lengths differ from the neck to the tail tip and differ between species, evidenced by extreme differences in mouse and jerboa tails. Here, Weber and colleagues identify cellular mechanisms and candidate genes that shape vertebral proportion.