Regulation and function of the Cdk5/QKI pathway in oligodendroglial development Open Access

Bankston, Andrew Nathaniel (2013)

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Proper development of oligodendroglia (OL), the cells of the central nervous system that provide myelin and neurotrophic and metabolic support to axons, is critical for normal brain function. Impaired OL function in the pathogenesis of numerous brain diseases originally attributed to neuronal defects, such as Alzheimer's disease and schizophrenia, has become increasingly recognized. Furthermore, signaling pathways performing critical functions in neuronal development, such as Cdk5, are found to play key roles in OL development. However, OL-specific regulators and functional targets of Cdk5 activity remain elusive. In this dissertation, mechanisms regulating Cdk5 activation in OLs and functional targets mediating Cdk5-dependent OL development, myelination, and myelin repair are explored.

We first examined whether neurons and OLs employ similar or distinct mechanisms to regulate Cdk5 activity. We showed that in contrast to neurons that harbor high levels of two Cdk5 activators, p35 and p39, OLs express abundant p39 but negligible p35. We found that specific knockdown of p39 by siRNA significantly attenuates Cdk5 activity and OL differentiation without affecting p35. Finally, we detected that expression of p39, but not p35, is increased during differentiation and myelin repair, and remyelination is impaired in p39-/- mice.

We next investigated whether and how p39-dependent Cdk5 activation targets key proteins known to promote OL differentiation. We discovered that the selective RNA-binding protein QKI, which is critical for OL and myelin development, is a target of Cdk5. Specifically, T243, shared by all QKI isoforms that display distinct nuclear-cytoplasmic distribution, is an important site of Cdk5-dependent phosphorylation. We further demonstrated that myristoylation of p39 restricts the majority of Cdk5 activity to the cytoplasm. Moreover, T243 phosphorylation of cytoplasmic QKI isoforms by Cdk5 induces nuclear translocation and enhanced QKI function in promoting OL differentiation.

Together, these studies uncovered novel mechanisms that specifically underlie Cdk5 activation in OLs during normal development and myelin lesion repair. Furthermore, we provided the first evidence connecting Cdk5 signaling with the posttranscriptional cascade under control of QKI. Further investigation of the functional interplay between Cdk5 and QKI pathway may ultimately help to develop new strategies against neurological disorders involving OL impairment.

Table of Contents

Chapter 1: Introduction to Dissertation...1

1.1 Oligodendroglial and myelin development and dysfunction...5

1.1.1 Myelin is essential for central nervous system function...5

1.1.2 Oligodendroglial lineage development...12

1.1.3 Emerging evidence for oligodendroglia and myelin impairment in neurodegeneration...19

1.1.4 Enhancing OL lineage progression for myelin repair...24

1.2 Cyclin-dependent kinase 5 (Cdk5) is essential for neuronal and oligodendroglial development...26

1.2.1 Regulation of Cdk5 activity...26

1.2.2 Cdk5 is essential for neuronal development...33

1.2.3 Emerging evidence of crucial roles for Cdk5 in oligodendroglial and myelin development...36

1.2.4 Cdk5 in neurodegeneration...37

1.3 The function of the selective RNA-binding protein QKI in oligodendroglial and myelin development...41

1.3.1 QKI is essential for oligodendroglial lineage development and CNS myelinogenesis...41

1.3.2 The balance of nuclear and cytoplasmic QKI isoforms regulates oligodendroglial development...43

1.3.3 QKI as a Signal Transduction Activation of RNA (STAR) family member...48

1.4 Summary...52

Chapter 2: p39, the Primary activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, is Essential for Oligodendroglial Differentiation and Myelin Repair...56

2.1 Introduction...57

2.2 Results...59

2.2.1 Distinct expression profiles of p35 and p39 in neurons and OLs...59

2.2.2 p39, but not p35, is upregulated during OL and myelin development...65

2.2.3 p39-dependent Cdk5 activation is essential for OL differentiation...68

2.2.4 p39 is upregulated during remyelination and essential for repair of myelin lesions...79

2.3 Discussion...84

Chapter 3: Phosphorylation of Cytoplasmic QKI by Cdk5 Induces Nuclear Translocation and Promotes Oligodendroglia Differentiation...88

3.1 Introduction...89

3.2 Results...91

3.2.1 Myristoylation retains p39 in the cytoplasm of oligodendroglia...91

3.2.2 Threonine 243 is the major site of Cdk5-dependent QKI phosphorylation...94

3.2.3 Threonine 243 phosphorylation of cytoplasmic QKI induces nuclear translocation...98

3.2.4 Threonine 243 phosphorylation of cytoplasmic QKI promotes oligodendroglial differentiation...109

3.3 Discussion...112

Chapter 4: Conclusions and Future Directions...117 Chapter 5: Materials and Methods...133

Chapter 6: References...144

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