GRIN3A and MAPT stimulate nerve overgrowth in macrodactyly

Abstract

As an uncommon and congenital condition, macrodactyly is characterized by an increase in the size of all the elements or structures of the digits or toes; however, the underlying pathogenesis remains to be fully elucidated. In the present study, the gene expression profiles of abnormal nerves were examined in three patients with macrodactyly using microarray analysis to identify potential genes contributing to nerve overgrowth. Gene expression profiling in the nerve tissue samples were scanned using the microarray and the differentially expressed genes were verified at the transcription level using reverse transcription-quantitative polymerase chain reaction analysis. Western blot analysis was used to determine the expression of target genes at the translational level. To confirm the upregulated genes during the process of nerve proliferation, SH-SY5Y cells were induced to differentiate into a neuronal-like phenotype using retinoic acid. A total of 165 genes showed significant changes (5-fold) in gene expression, which may be associated with the development of limbs in macrodactyly. Glutamate ionotropic receptor NMDA 3A (GRIN3A) and microtubule-associated protein tau (MAPT) were identified as important contributors in promoting nerve overgrowth. Furthermore, it was identified that GRIN3A and MAPT were regulated by the cAMP-protein kinase A and extracellular signal-regulated kinase 1/2 pathways, respectively. The identification of genes expressed at high levels in macrodactyly may reveal potential factors, which contribute to abnormal nerve proliferation and underpin the pathogenesis of macrodactyly, and provide potential application targets in nerve tissue regeneration engineering.