Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Area of Science:

• Developmental Biology
• Neuroscience
• Genetics

Background:

• Closed spinal dysraphisms, including terminal myelocystocele, are poorly understood neural tube (NT) defects affecting the distal spine.
• A specific NT closure site, Closure 5, has been identified in the distal spine of mice.

Purpose of the Study:

• To investigate the role of Fibroblast Growth Factor Receptor 1 (FGFR1) signaling in the formation of Closure 5 and posterior neuropore (PNP) closure.
• To characterize the resulting NT defects and their resemblance to human terminal myelocystocele.

Main Methods:

• Morphological analysis of mouse and human caudal-most closing posterior neuropore (PNP).
• Pharmacological blockade of FGF signaling in cultured mouse embryos.
• Conditional genetic deletion of Fgfr1 in caudal embryonic tissues using Cdx2Cre mice.
• Histological analysis of spinal cord development and gene expression (SHH, FOXA2, OLIG2, PAX3).

Main Results:

• Closure 5 formation occurs in a region of active FGF signaling; FGF receptor blockade impairs its formation.
• FGFR1 disruption in mice diminishes neuroepithelial proliferation, impairs Closure 5 formation, and delays PNP closure.
• Fgfr1-disrupted embryos exhibit distal NT dilation, resembling terminal myelocystocele, with ventral spinal cord flattening and progressive loss of ventral NT domains (SHH, FOXA2, OLIG2), leading to a dorsalized NT (PAX3).

Conclusions:

• FGFR1 signaling is essential for proper Closure 5 formation and posterior neuropore closure.
• Disruption of FGFR1 signaling can lead to terminal myelocystocele-like phenotypes after NT closure due to localized spinal mis-patterning.
• This study highlights the critical role of FGFR1 in distal spinal cord development and provides insights into the etiology of spinal dysraphisms.