Effects of IKAP-hELP1 Deficiency on Gene Expression in Differentiating Neuroblastoma Cells: Implications for Familial DysautonomiaReportar como inadecuado




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Familial dysautonomia FD is a developmental neuropathy of the sensory and autonomous nervous systems. The IKBKAP gene, encoding the IKAP-hELP1 subunit of the RNA polymerase II Elongator complex is mutated in FD patients, leading to a tissue-specific mis-splicing of the gene and to the absence of the protein in neuronal tissues. To elucidate the function of IKAP-hELP1 in the development of neuronal cells, we have downregulated IKBKAP expression in SHSY5Y cells, a neuroblastoma cell line of a neural crest origin. We have previously shown that these cells exhibit abnormal cell adhesion when allowed to differentiate under defined culture conditions on laminin substratum. Here, we report results of a microarray expression analysis of IKAP-hELP1 downregulated cells that were grown on laminin under differentiation or non-differentiation growth conditions. It is shown that under non-differentiation growth conditions, IKAP-hELP1 downregulation affects genes important for early developmental stages of the nervous system, including cell signaling, cell adhesion and neural crest migration. IKAP-hELP1 downregulation during differentiation affects the expression of genes that play a role in late neuronal development, in axonal projection and synapse formation and function. We also show that IKAP-hELP1 deficiency affects the expression of genes involved in calcium metabolism before and after differentiation of the neuroblastoma cells. Hence, our data support IKAP-hELP1 importance in the development and function of neuronal cells and contribute to the understanding of the FD phenotype.



Autor: Rachel Cohen-Kupiec, Metsada Pasmanik-Chor, Varda Oron-Karni, Miguel Weil

Fuente: http://plos.srce.hr/



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