Biomedical subjects

Li Ku

Publications and source records attributed to Li Ku.

6 recordsLinked to original sources

PubMed2006

QKI binds MAP1B mRNA and enhances MAP1B expression during oligodendrocyte development.

Microtubule-associated protein 1B (MAP1B) is essential for neural development. Besides the abundant expression in neurons, MAP1B recently was found in myelinating oligodendroglia. Moreover, MAP1B deficiency causes delayed myelin development, suggesting the functional importance of MAP1B in oligodendroglia. However, molecular mechanisms that control MAP1B expression in oligodendroglia remain elusive. We report here that MAP1B mRNA is markedly up-regulated in the oligodendroglia cell line CG4 upon induced differentiation, leading to elevated MAP1B protein production. A coordinated regulation of homeoprotein transcription factors was observed during CG4 cell differentiation, which recapitulates the regulation in neurons that promotes MAP1B transcription. Hence, transcriptional regulation of MAP1B appears to be a common mechanism in both neurons and oligodendroglia. In addition, we found posttranscriptional regulation of MAP1B mRNA by the selective RNA-binding protein QKI in oligodendroglia. The 3'UTR of MAP1B mRNA interacts with QKI, and oligodendroglia-specific QKI-deficiency in the quakingviable mutant mice resulted in reduced MAP1B mRNA expression. Moreover, RNAi-mediated QKI-knockdown caused destabilization of the MAP1B mRNA in CG4 cells. Furthermore, forced expression of exogenous QKI was sufficient for promoting MAP1B expression. Because QKI is absent in neurons, QKI-dependent stabilization of MAP1B mRNA provides a novel mechanism for advancing MAP1B expression specifically in oligodendroglia during brain development.

Animals↗

PubMed2004

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.

Animals↗

PubMed2004

The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development.

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KO brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KO neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.

Animals↗

PubMed2003

Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors.

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein whose function is implicated in regulating protein synthesis of its mRNA targets. The lack of FMRP leads to abnormal synapse development in the brain and impaired learning/memory. Although FMRP is predominantly expressed in neurons of the adult brain, whether FMRP also functions in glia during early development remains elusive, since expression of FMRP in glia has not been rigorously examined. This is an important question because recent studies revealed important roles of glia in synaptic development. Here we report that in addition to the observed neuronal expression, FMRP expression is detected in oligodendroglia progenitor cells (OPCs), immature oligodendrocytes and oligodendroglia cell lines, where it interacts with a subgroup of oligodendrocyte-specific mRNAs, including the myelin basic protein (MBP) mRNA. FMRP expression gradually declines as oligodendrocytes differentiate in vitro and in the developing brain. The decline of FMRP expression during oligodendrocyte differentiation is associated with a vigorous up-regulation of the MBP protein. In addition, we show that the MBP 3'untranslated region (3'UTR) is necessary and sufficient for binding FMRP, and mediates translation inhibition of a reporter gene by FMRP specifically in oligodendrocytes. These results support the hypothesis that FMRP may participate in regulating translation of its bound mRNAs in oligodendroglia during early brain development.

Brain↗

PubMed2003

The quakingviable mutation affects qkI mRNA expression specifically in myelin-producing cells of the nervous system.

The genetic lesion in the quakingviable (qk(v)) mutant mice is a deletion 5' to the qkI gene, resulting in severe hypomyelination. qkI produces several QKI protein isoforms via alternative splicing of the C-terminal coding exons. In the qk(v)/qk(v) brain, immunostaining of QKI proteins is diminished in an isoform-differential manner with undefined mechanisms. We examined the expression of QKI protein isoforms and qkI mRNA isoforms in the qk(v)/qk(v) mutants and the non-phenotypic wt/qk(v) littermates. Our results indicated significant reduction of all qkI mRNA isoforms in the central and peripheral nervous system during active myelination without detectable post-transcriptional abnormalities. In the early stage of myelin development, qkI mRNAs are differentially reduced, which appeared to be responsible for the reduction of the corresponding QKI protein isoforms. The reduced qkI expression was a specific consequence of the qk(v) lesion, not observed in other hypomyelination mutants. Further more, no abnormal qkI expression was found in testis, heart and astroglia of the qk(v)/qk(v) mice, suggesting that the reduction of qkI mRNAs occurred specifically in myelin-producing cells of the nervous system. These observations suggest that diminished qkI expression results from deletion of an enhancer that promotes qkI transcription specifically in myelinating glia during active myelinogenesis.

Animals↗

PubMed2003

Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism.

The selective RNA-binding protein QKI is essential for myelination in the central nervous system (CNS). QKI belongs to the family of signal transduction activators of RNA (STARs), characteristic of binding RNA and signaling molecules, therefore is postulated to regulate RNA homeostasis in response to developmental signals. Here we report that QKI acts downstream of the Src family protein tyrosine kinases (Src-PTKs) during CNS myelination. QKI selectively interacted with the mRNA encoding the myelin basic protein (MBP). Such interaction stabilized MBP mRNA and was required for the rapid accumulation of MBP mRNA during active myelinogenesis. We found that the interaction between QKI and MBP mRNA was negatively regulated by Src-PTK-dependent phosphorylation of QKI. During early myelin development, tyrosine phosphorylation of QKI in the developing myelin drastically declined, presumably leading to enhanced interactions between QKI and MBP mRNA, which was associated with the rapid accumulation of MBP mRNA and accelerated myelin production. Therefore, developmental regulation of Src-PTK-dependent tyrosine phosphorylation of QKI suggests a novel mechanism for accelerating CNS myelinogenesis via regulating mRNA metabolism.

Amino Acid Sequence↗