Distinct effects of tubulin isotype mutations on neurite growth in<i>Caenorhabditis elegans</i>

Zheng, Chaogu; Diaz‐Cuadros, Margarete; Nguyen, Ken; Hall, David H.; Chalfie, Martin

doi:10.1091/mbc.e17-06-0424

Cited by 34 publications

(78 citation statements)

References 72 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neomorphic mutations had no effect on growth cone area, but increased average filopodial length (Figure 4, A, B, and D). This is consistent with neomorphic mutations causing increased neurite outgrowth in the touch receptor neurons (Zheng et al 2017). Antimorphic mutations resulted in reduced growth cone area and average filopodial length (Figure 4, A, B, and E), suggesting that MT destabilization reduces growth cone protrusion.…”

Section: Microtubules Are Required For Vd Growth Cone Protrusionsupporting

confidence: 81%

“…We find that unc-5 mutants display increased numbers of EBP-2::GFP puncta, representing MT + ends, that correlate with increased protrusion. We find that expression of mutant forms of tba-1 and tbb-1 predicted to destabilize microtubules (Zheng et al 2017) caused reduced protrusion, as did treatment with the MT-destabilizing compound colchicine. Furthermore, colchicine treatment reduced protrusion in unc-5 mutants.…”

Section: Vd Growth Cone Protrusion Requires Microtubulesmentioning

confidence: 75%

“…The microtubule-destabilizing compound colchicine was previously shown to suppress ectopic protrusions caused by stabilizing neomorphic tubulin mutations in the touch receptor neurons (Zheng et al 2017). Wild-type VD growth cones displayed significantly reduced growth cone area and filopodial protrusion when animals were grown on 1 mM colchicine ( Figure 5, A, B, and D), with accompanying VD/DD axon guidance defects ( Figure 5, G and I).…”

Section: Microtubules Are Required For Vd Growth Cone Protrusionmentioning

confidence: 90%

“…Missense mutations in the touch-receptor-specific mec-7/b tubulin and mec-12/a tubulin genes had effects on touch cell function and neurite outgrowth that did not resemble simple loss of function of the genes (Zheng et al 2017). Phenotypic analysis and treatment with colchicine and paclitaxel led to the classification of these mutations as neomorphic, which resulted in microtubule stabilization, and antimorphic, which resulted in destabilization (Zheng et al 2017).…”

Section: Microtubules Are Required For Vd Growth Cone Protrusionmentioning

confidence: 99%

See 3 more Smart Citations

Control of Growth Cone Polarity, Microtubule Accumulation, and Protrusion by UNC-6/Netrin and Its Receptors in Caenorhabditis elegans

Gujar¹,

Sundararajan²,

Stricker³

et al. 2018

Genetics

View full text Add to dashboard Cite

UNC-6/Netrin has a conserved role in dorsal-ventral axon guidance, but the cellular events in the growth cone regulated by UNC-6/Netrin signaling during outgrowth are incompletely understood. Previous studies showed that, in growth cones migrating away from UNC-6/Netrin, the receptor UNC-5 regulates growth cone polarity, as observed by polarized F-actin, and limits the extent of growth cone protrusion. It is unclear how UNC-5 inhibits protrusion, and how UNC-40 acts in concert with UNC-5 to regulate polarity and protrusion. New results reported here indicate that UNC-5 normally restricts microtubule (MT) + end accumulation in the growth cone. Tubulin mutant analysis and colchicine treatment suggest that stable MTs are necessary for robust growth cone protrusion. Thus, UNC-5 might inhibit protrusion in part by restricting growth cone MT accumulation. Previous studies showed that the UNC-73/Trio Rac GEF and UNC-33/CRMP act downstream of UNC-5 in protrusion. Here, we show that UNC-33/CRMP regulates both growth cone dorsal asymmetric F-actin accumulation and MT accumulation, whereas UNC-73/Trio Rac GEF activity only affects F-actin accumulation. This suggests an MT-independent mechanism used by UNC-5 to inhibit protrusion, possibly by regulating lamellipodial and filopodial actin. Furthermore, we show that UNC-6/Netrin and the receptor UNC-40/DCC are required for excess protrusion in mutants, but not for loss of F-actin asymmetry or MT + end accumulation, indicating that UNC-6/Netrin and UNC-40/DCC are required for protrusion downstream of, or in parallel to, F-actin asymmetry and MT + end entry. F-actin accumulation might represent a polarity mark in the growth cone where protrusion will occur, and not protrusive lamellipodial and filopodial actin Our data suggest a model in which UNC-6/Netrin first polarizes the growth cone via UNC-5, and then regulates protrusion based upon this polarity (the polarity/protrusion model). UNC-6/Netrin inhibits protrusion ventrally via UNC-5, and stimulates protrusion dorsally via UNC-40, resulting in dorsally-directed migration. The polarity/protrusion model represents a novel conceptual paradigm in which to understand axon guidance and growth cone migration away from UNC-6/Netrin.

show abstract

Section: Microtubules Are Required For Vd Growth Cone Protrusionsupporting

confidence: 81%

Section: Vd Growth Cone Protrusion Requires Microtubulesmentioning

confidence: 75%

Section: Microtubules Are Required For Vd Growth Cone Protrusionmentioning

confidence: 90%

Section: Microtubules Are Required For Vd Growth Cone Protrusionmentioning

confidence: 99%

See 2 more Smart Citations

Control of Growth Cone Polarity, Microtubule Accumulation, and Protrusion by UNC-6/Netrin and Its Receptors in Caenorhabditis elegans

Gujar¹,

Sundararajan²,

Stricker³

et al. 2018

Genetics

View full text Add to dashboard Cite

show abstract

“…While functional evidence was present for a minority of the variants 5,30 , most mutational effects are based on localization-dependent predictions. As a template we used 51 already classified TUBA1A variants 31 likely affecting the binding of microtubule associated proteins (“MAP binding”) or motor proteins, the tubulin folding (“Tubulin folding”), heterodimer and microtubule stability (“Intradimer interaction” and “Longitudinal interaction”) the formation of the hollow tubular structure of the microtubule (“Lateral interaction”) 32,33 or microtubule dynamics, protein folding and heterodimer stability (“GTP [Guanosintriphosphat] binding”) 29,32 . The specific detrimental effect of variants facing the luminal protein surface (“Lumen facing”) is currently unknown.…”

Section: Methodsmentioning

confidence: 99%

The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

Hebebrand

Hüffmeier

Uebe

et al. 2018

Preprint

View full text Add to dashboard Cite

Background:The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. Results:In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (70%), although reporting was incomplete in the different studies. We identified a total of 121 distinct variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a threedimensional protein modelling, 38.6% of all disease causing variants including those in the C-terminal region are predicted to affect binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication. Conclusions:With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

show abstract

Maintaining essential microtubule bundles in meter-long axons: a role for local tubulin biogenesis?

Pinho-Correia

Prokop

2023

Brain Research Bulletin

View full text Add to dashboard Cite

Distinct effects of tubulin isotype mutations on neurite growth inCaenorhabditis elegans

Cited by 34 publications

References 72 publications

Control of Growth Cone Polarity, Microtubule Accumulation, and Protrusion by UNC-6/Netrin and Its Receptors in Caenorhabditis elegans

Control of Growth Cone Polarity, Microtubule Accumulation, and Protrusion by UNC-6/Netrin and Its Receptors in Caenorhabditis elegans

The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

Maintaining essential microtubule bundles in meter-long axons: a role for local tubulin biogenesis?

Contact Info

Product

Resources

About