Wednesday, April 2, 2025
4/2/2025
Characterizing the cell-of-origin for NF1 dystrophic scoliosis - ABSTRACT The most prevalent skeletal condition in patients with neurofibromatosis type 1 (NF1) is dystrophic scoliosis, a debilitating and disfiguring disorder characterized by severe, short-segment angulation of the spine leading to multiple clinical complications. Clinical management is currently limited to invasive and repeated surgeries, and case presentations are very variable, suggesting that underlying etiology is different from one patient to the next. The lack of effective treatment to prevent or treat this condition reflects the fact that the pathophysiology of NF1 dystrophic scoliosis is unknow. The novel scientific idea introduced in this proposal is that Nf1 loss-of-function in the intervertebral disc (IVD) affects the formation and maintenance of IVD-vertebra unit, and that the cell-of-origin and timing of Nf1 loss-of- function during development dictate severity and speed of progression of NF1 scoliosis, in clinical cases where dystrophic scoliosis is not associated with paraspinal neurofibromas. This hypothesis is based on the severe IVD and vertebral dysplasia observed in mice lacking Nf1 in all cells of the IVD, and on the report of a clinical case of NF1 dystrophic scoliosis associated with NF1 loss-of-heterozygosity in IVD cells. To address this hypothesis and to identify the cell-of-origin causing this IVD and spine dysplasia, we will characterize the formation and maintenance of the IVD-vertebra units in embryos lacking Nf1 in either notochordal cells/nucleus pulposus cells or in sclerotomal progenitor cells that give rise to cartilage end plates, annulus fibrosus and vertebral bodies. In Aim 1, the generated conditional mutant mice will be compared at several developmental stages to characterize the consequences of Nf1 loss in each IVD compartment and upon Nf1 deletion at embryonic versus postnatal stage. In Aim 2, we will obtain an unbiased list of candidate genes and pathways as foundation to explore how the loss of Nf1 in the different IVD compartments affects formation and maintenance of the IVD-vertebra units, using laser-assisted microdissection of the IVD and RNA sequencing. Doing so and coupled to findings from Aim 1, we aim at understanding how Nf1 loss-of-function in specific compartments of the IVD alters each IVD compartment and the interactions between adjacent ones to contribute to the initiation and severity of NF1 dystrophic scoliosis. This knowledge will be the foundation to discover new and targeted options for a personalized management of patients with NF1 dystrophic scoliosis.
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