Functional coordination of alternative splicing in the mammalian central nervous system

Matthew Fagnani^*¹^,2 , Yoseph Barash^*¹^,3 , Joanna Y Ip¹^,2 , Christine Misquitta¹ , Qun Pan¹ , Arneet L Saltzman¹^,2 , Ofer Shai³ , Leo Lee³ , Aviad Rozenhek⁴ , Naveed Mohammad² , Sandrine Willaime-Morawek² , Tomas Babak¹^,2 , Wen Zhang¹^,2 , Timothy R Hughes¹^,2 , Derek van der Kooy² , Brendan J Frey¹^,3 and Benjamin J Blencowe¹^,2

¹Banting and Best Department of Medical Research, Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario, Canada. M5S 3E1

²Department of Molecular and Medical Genetics, Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario, Canada. M5S 3E1

³Department of Electrical and Computer Engineering, University of Toronto, 40 St. George's Street, Toronto, Ontario, Canada

⁴School of Computer Science and Engineering, Hebrew University, Jerusalem 91904, Israel

author email corresponding author email* Contributed equally

Genome Biology 2007, 8:R108doi:10.1186/gb-2007-8-6-r108


Published:	12 June 2007

Subject areas: Neurobiology, Molecular biology, Bioinformatics, Genome studies

Abstract

Background

Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood.

Results

Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues.

Conclusion

Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS.