Genetic variations regulate alternative splicing in the 5' untranslated regions of the mouse glioma-associated oncogene 1, Gli1.
BACKGROUND
Alternative splicing is one of the key mechanisms that generate biological diversity. Even though alternative splicing also occurs in the 5' and 3' untranslated regions (UTRs) of mRNAs, the understanding of the significance and the regulation of these variations is rather limited.


RESULTS
We investigated 5' UTR mRNA variants of the mouse Gli1 oncogene, which is the terminal transcriptional effector of the Hedgehog (HH) signaling pathway. In addition to identifying novel transcription start sites, we demonstrated that the expression ratio of the Gli1 splice variants in the 5' UTR is regulated by the genotype of the mouse strain analyzed. The GT allele, which contains the consensus intronic dinucleotides at the 5' splice site of intron 1B, favors exon 1B inclusion, while the GC allele, having a weaker 5' splice site sequence, promotes exon 1B skipping. Moreover, the alternative Gli1 5' UTRs had an impact on translational capacity, with the shorter and the exon 1B-skipped mRNA variants being most effective.


CONCLUSIONS
Our findings implicate novel, genome-based mechanisms as regulators of the terminal events in the mouse HH signaling cascade.
Palaniswamy
Ramesh
R
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-14157 Sweden.
Teglund
Stephan
S
Lauth
Matthias
M
Zaphiropoulos
Peter G
PG
Shimokawa
Takashi
T
D020121:5' Untranslated Regions; D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology; D047108:Embryonic Development; D005091:Exons; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D007438:Introns; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D024363:Transcription Initiation Site; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1
D020121:5' Untranslated Regions; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1