严重型SMA小鼠血管发育缺陷的分子机制研究

Objective: To explore the molecular mechanism of vascular developmental defects caused by SMN deficiency using spinal muscular atrophy (SMA) mouse models, which may identify key downstream genes, leading to not only better understanding of the disease but new gene targets for therapeutic intervention. Methods: Using q-PCR to detect differences in mRNA abundance of Sox7, Sox17 and Sox18 (SoxF), key genes associated with vascular development, as well as their downstream targets between SMA mice and heterozygote controls in various tissues at different time points. Splicing changes of Sox17, which normally expresses several transcripts due to alternative splicing, were analyzed by RT-PCR. Results: On days 3 (P3) and 4 (P4) after birth, expression of SoxF and its downstream target genes in the small intestine, brain and heart tissues of severe SMA mice did not change significantly. However, the above genes are markedly down-regulated on P3 and P4 in lung, liver and muscle tissues, with lung tissues showing the greatest decrease (>50%). The eyeball is a tissue with the highest vascular density. We observed significant down-regulation of SoxF genes and their downstream target genes in eyeball tissues between P2 and P5. No splicing alterations were observed for the Sox17 gene. Conclusion: SoxF genes as well as its downstream target genes were downregulated, which gives rise to vascular development defects in SMA mice. The expression changes of these genes are tissue dependent. The expression changes of the Sox17 gene occur at the transcriptionlevel and involve no splicing alterations.