Alternative splicing is a crucial mechanism expanding transcriptome and proteome diversity, with post-translational modifications further enhancing this complexity. Our research focuses on Neurofibromatosis-1 (NF-1), caused by mutations in the NF1 gene that encodes neurofibromin and impacts both learning as well as glioblastoma development. Major alternate exons in the NF1 mRNA are exon31, involved in the production of transcripts and isoforms with different RasGAP potencies; and exon51, which bears a nuclear localization signal (NLS) leading to the production of NLS variants that enter the nucleus. Our previous work has revealed that NLS neurofibromins also function as Microtubule Associated Proteins (MAPs) in astrocytes, regulating spindle assembly, chromosome segregation, and genome transmission. Induction of exon51 skipping using short antisense oligonucleotides (SSOs) in chick embryo primary neuronal cultures, we found that ΔNLS neurofibromins are robust RasGAPs, influencing H-Ras activation amplitude and duration, as well as its membrane mobility. In addition, RNA-sequencing analysis showed that NLS neurofibromin depletion impacts the transcriptome related to microtubule cytoskeleton and synapse formation, revealing the complex role of neurofibromin isoforms in neuronal differentiation and synaptogenesis. Confocal imaging and IMARIS analysis revealed altered growth cone phenotypes, including increased actin filopodia length and volume in early post-mitotic neurons. Hence, this research contributes to understanding neurofibromin's multifunctional role in neurons as RasGAPs and as MAPs, while, as splicing modulation with SSOs has proven invaluable in the therapy of monogenic diseases, it providing insights for potential novel therapeutic interventions in NF-1.