Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in posttranscriptional regulation.
Fyn protein-tyrosine kinase (PTK), a member of the Src-PTK family, is essential for myelin development in the central nervous system (CNS). The absence of Fyn activity results in defects in the morphogenesis of oligodendrocyte precursors (OPCs) and CNS hypomyelination. However, molecular mechanisms for Fyn to control CNS myelinogenesis remain elusive. Here we show that Fyn-PTK is significantly up-regulated in early OPC differentiation, concentrated in the compact myelin, and declines during myelin development. Despite the high levels of Fyn-PTK expression during early OPC differentiation, Fyn deficiency does not affect the expression of mRNAs that encode myelin structural proteins, including that for the myelin basic protein (MBP), until postnatal day 13 (P13). However, the accumulation rate of MBP mRNA is significantly attenuated during the most active period of myelinogenesis (P13 and P20). Interestingly, the absence of Fyn causes a preferential reduction of the exon-2 containing MBP mRNA isoforms derived from alternative splicing, providing the first evidence that Fyn is required for posttranscriptional regulation of MBP. Consistent with this idea, Fyn phosphorylates the selective RNA-binding protein QKI, which likely modulates the activity of QKI in binding and stabilizing the MBP mRNA. Furthermore, Fyn deficiency exerts an opposing influence on MBP isoform patterning in comparison to that by QKI deficiency. These observations collectively suggest that Fyn plays critical roles in promoting accelerated MBP expression during myelinogenesis in a MBP isoform-preferential manner, and QKI may act in the same pathway downstream of Fyn for MBP mRNA homeostasis.
Lu
Zifan
Z
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Ku
Li
L
Chen
Yuntao
Y
Feng
Yue
Y
D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008821:Mice, Quaking; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
D004676:Myelin Basic Protein; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C098217:Qk protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases