Abstract
Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. Elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA- 7 may be responsible for this destabilization.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2786-2801 |
| Number of pages | 16 |
| Journal | Molecular Biology of the Cell |
| Volume | 28 |
| Issue number | 21 |
| DOIs | |
| State | Published - Oct 15 2017 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans. / Zheng, Chaogu; Diaz-Cuadros, Margarete; Nguyen, Ken C.Q.; Hall, David H.; Chalfie, Martin.
In: Molecular Biology of the Cell, Vol. 28, No. 21, 15.10.2017, p. 2786-2801.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
AU - Zheng, Chaogu
AU - Diaz-Cuadros, Margarete
AU - Nguyen, Ken C.Q.
AU - Hall, David H.
AU - Chalfie, Martin
PY - 2017/10/15
Y1 - 2017/10/15
N2 - Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. Elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA- 7 may be responsible for this destabilization.
AB - Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. Elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA- 7 may be responsible for this destabilization.
UR - http://www.scopus.com/inward/record.url?scp=85031280281&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031280281&partnerID=8YFLogxK
U2 - 10.1091/mbc.E17-06-0424
DO - 10.1091/mbc.E17-06-0424
M3 - Article
C2 - 28835377
AN - SCOPUS:85031280281
VL - 28
SP - 2786
EP - 2801
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 21
ER -