Neurofilament-dependent Radial Growth of Motor Axons and Axonal Organization of Neurofilaments Does Not Require the Neurofilament Heavy Subunit (NF-H) or Its Phosphorylation

Rao, M. Subba; Houseweart, Megan K.; Williamson, Toni; Crawford, Thomas O.; Folmer, Janet; Cleveland, Don W.

doi:10.1083/jcb.143.1.171

Cited by 141 publications

(162 citation statements)

References 59 publications

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“…These result in sidearm formation, increased inter-neurofilament spacing, radial growth of axons, and increased conduction velocity (24 -26). More recent studies, however, of NF-H null mice, or mice transfected with a NF-H tailless mutant, suggest that neither NF-H nor its phosphorylated tail are essential to the above neuronal properties (27,28). Nevertheless, deregulation of NF-M and NF-H tail domain phosphorylation is correlated with some pathologies seen in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) in which tail domain phosphorylation occurs abnormally in perikarya (29 -31).…”

Section: Neurofilament (Nf)mentioning

confidence: 99%

Phosphorylation of the Head Domain of Neurofilament Protein (NF-M)

Zheng

Veeranna³

et al. 2003

Journal of Biological Chemistry

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In neurons the phosphorylation of neurofilament (NF) proteins NF-M and NF-H is topographically regulated.Although kinases and NF subunits are synthesized in cell bodies, extensive phosphorylation of the KSP repeats in tail domains of NF-M and NF-H occurs primarily in axons. The nature of this regulation, however, is not understood. As obligate heteropolymers, NF assembly requires interactions between the core NF-L with NF-M or NF-H subunits, a process inhibited by NF head domain phosphorylation. Phosphorylation of head domains at protein kinase A (PKA)-specific sites seems to occur transiently in cell bodies after NF subunit synthesis. We have proposed that transient phosphorylation of head domains prevents NF assembly in the soma and inhibits tail domain phosphorylation; i.e. assembly and KSP phosphorylation in axons depends on prior dephosphorylation of head domain sites. Deregulation of this process leads to pathological accumulations of phosphorylated NFs in the soma as seen in some neurodegenerative disorders. To test this hypothesis, we studied the effect

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Section: Neurofilament (Nf)mentioning

confidence: 99%

Phosphorylation of the Head Domain of Neurofilament Protein (NF-M)

Zheng

Veeranna³

et al. 2003

Journal of Biological Chemistry

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“…However, the role of IFs in the developing CNS has been less studied. IFs are differentially expressed during neuronal development; however, the type IV IFs (Box 1) are dispensable as none of the mouse knockout models generated for type IV IFs (Box 2) displays gross developmental defects (Elder et al, 1998;Levavasseur et al, 1999;McCullagh et al, 2008;Rao et al, 1998;Zhu et al, 1997). NFs are known to affect the development of a subset of neuronal cell types (for a review, see Lariviere and Julien, 2004).…”

Section: Remodelling Of If Proteins In Neuronsmentioning

confidence: 99%

Insights into intermediate filament regulation from development to ageing

Hyder

Isoniemi

Torvaldson

et al. 2011

Journal of Cell Science

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SummaryIntermediate filament (IF) proteins comprise a large family with more than 70 members. Initially, IFs were assumed to provide only structural reinforcement for the cell. However, IFs are now known to be dynamic structures that are involved in a wide range of cellular processes during all stages of life, from development to ageing, and during homeostasis and stress. This Commentary discusses some lesser-known functional and regulatory aspects of IFs. We specifically address the emerging roles of nestin in myogenesis and cancer cell migration, and examine exciting evidence on the regulation of nestin and lamin A by the notch signalling pathway, which could have repercussions for our understanding of the roles of IF proteins in development and ageing. In addition, we discuss the modulation of the post-translational modifications of neuronally expressed IFs and their protein-protein interactions, as well as IF glycosylation, which not only has a role in stress and ageing, but might also regulate IFs during development. Although many of these recent findings are still preliminary, they nevertheless open new doors to explore the functionality of the IF family of proteins. Journal of Cell ScienceCdk5 is associated with nestin in myoblasts, neuronal precursor cells (Sahlgren et al., 2003) and human podocytes (Bertelli et al., 2007). Cdk5 phosphorylates nestin, and this phosphorylation regulates the organization of nestin filaments (Box 2) during myogenic differentiation (Sahlgren et al., 2003). Interestingly, the interaction between nestin and Cdk5 is not limited to a typical kinase-substrate relationship. In neuronal precursor cells, nestin forms a scaffold for Cdk5 and the Cdk5 activator p35, thereby sequestering them to the cytoplasm, which consequently inhibits the proapoptotic function of Cdk5 during oxidative stress (Sahlgren et al., 2006). In turn, it has recently been demonstrated that Cdk5 is targeted by protein kinase C- (PKC) during myogenesis (de Thonel et al., 2010). PKC is essential for proper myoblast differentiation. It targets Cdk5 by phosphorylating p35 at a site that triggers the activation of calpains, which then cleave p35 into p25. The cleavage of p35 into p25 creates a more stable protein fragment, and this fragment is capable of sustained Cdk5 activation, consequently promoting nestin reorganization (Fig. 1,. An earlier study, in cultured neurons, demonstrated that Cdk5 is also able to regulate p35 by phosphorylation, thereby protecting it from calpain-mediated cleavage (Kamei et al., 2007). Furthermore, a recent study has shown that nestin has the capacity to modulate Cdk5-mediated differentiation and terminal organization of muscle cells (Pallari et al., 2011) (Fig. 1, left-hand side). Taken together, these results suggest that a balance between Cdk5 and PKC is important for proper myogenic differentiation, as they show that disturbance of the PKC-Cdk5-nestin signalling pathway leads to nestin reorganization and impedes myoblast differentiation, implying that nestin also plays a k...

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“…In fact, the nervous system of these tau-deficient animals is immunohistologically normal and cultured hippocampal neurons prepared from these mice show that axonal Opinion elongation is unaffected [24]. Furthermore, knockout mice for neurofilament subunits also do not show any overt behavioral phenotype or gross structural defects in the nervous system [74,75]. The fact that knockout animals for tau and neurofilament subunits do not present alterations of neuronal function suggests that NFT formation, and a consequent microtubule disorder, is not likely to be a cause of neurodegeneration in AD.…”

mentioning

confidence: 99%