The corpus callosum is the principal telencephalic commissure and forms the largest axonal tract in the human brain. Developmental absence (or agenesis) of the corpus callosum occurs in over 50 different congenital syndromes, affecting approximately 1 in 4000 live births. Importantly, the majority of callosal disconnection syndromes have profound consequences on normal cognition.
Mutations in the Fibroblast growth factor receptor (FGFR)1 and FGFR2 genes are some of the few known human autosomal dominant mutations that result in callosal agenesis. FGFR genes encode transmembrane-bound receptor tyrosine kinase proteins, which bind small secreted FGF ligand proteins in order to transduce multiple intracellular signalling pathways. Developmental FGF signalling is therefore likely to be a key regulator of callosal development; however, the precise role of FGF signalling in this process is poorly understood. To address this, an in-depth analysis of the expression and function of Fgf signalling molecules was performed throughout the development of the murine telencephalic commissures, and their underlying substrate, the telencephalic midline.
After initial axonal growth, telencephalic commissural axons must project through the telencephalic midline in order to reach contralateral neuronal targets. This region is a highly dynamic developmental structure, primarily comprising neurons and astroglia, which if perturbed, can significantly disrupt commissure development. Furthermore, the midline is molecularly enriched for multiple chemotropic cues, which direct the pathfinding of commissural axons within this region. Using in vivo gene knockdown and overexpression paradigms in mice, multiple modes of Fgf signalling were identified in the formation of the telencephalic midline and commissure formation. This approach demonstrated the secreted ligand Fgf8 regulates multiple processes throughout the development of this system, including the differentiation of astroglia throughout the telencephalon, interhemispheric fusion and commissural axon guidance of the corpus callosum and hippocampal commissure.
These results provide crucial insights into the molecular regulation of developmental mechanisms that underlie the formation of the telencephalic midline and its commissures. Additionally, novel evidence is presented that pertains to how astroglial cell types are initially generated in the telencephalon. Taken together, these results inform our understanding of the aetiology underlying callosal agenesis in humans, with particular reference to the callosal abnormalities observed in FGFR syndromes.