Limits...
Defective Gpsm2/G α i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

View Article: PubMed Central - PubMed

ABSTRACT

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

No MeSH data available.


Gpsm2 mutations affect stereocilia elongation and neuronal outgrowth by regulating actin dynamics at tip complexes.Mechanistic model for Gpsm2-dependent stereocilia elongation and neuronal outgrowth. Gpsm2 accumulates at the tip complex of both structures via the myosin 15 motor protein in stereocilia and a comparable motor protein in filopodia. Gpsm2-dependent macromolecular protein complexes modulate actin dynamics at the tip of stereocilia (growing end) or the leading edge of the growth cone, participating respectively in the elongation and motility of the two structures. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5385604&req=5

f9: Gpsm2 mutations affect stereocilia elongation and neuronal outgrowth by regulating actin dynamics at tip complexes.Mechanistic model for Gpsm2-dependent stereocilia elongation and neuronal outgrowth. Gpsm2 accumulates at the tip complex of both structures via the myosin 15 motor protein in stereocilia and a comparable motor protein in filopodia. Gpsm2-dependent macromolecular protein complexes modulate actin dynamics at the tip of stereocilia (growing end) or the leading edge of the growth cone, participating respectively in the elongation and motility of the two structures. See text for details.

Mentions: Myosin 15 is the molecular motor responsible for delivering whirlin and Eps8 to the tips of actin-rich stereocilia and this ternary complex is required for elongation of nascent stereocilia. Our results show that myosin 15 and whirlin are also required for trafficking Gpsm2 and Gαi3, two new members of the stereocilia tip complex, an electron-dense structure believed to contain proteins that regulate actin polymerization (Fig. 9). Accordingly, when myosin 15 is non-functional, Gpsm2 and Gαi3 (this study), as well as whirlin17 and Eps8 (refs 19, 22) are all absent from the stereocilia tips. On the other hand, when Whrn, Gpsm2 or Gnai3 are mutated, myosin 15 still accumulates at the tips of short abnormal stereocilia. The failure of Whrn, Gpsm2 and Gnai3 cKOs stereocilia to elongate despite the localization of myosin 15, suggests that these proteins assemble in a macromolecular complex (including Eps8) to regulate actin polymerization at the stereocilia tips. Interestingly, it was recently shown that the distribution of whirlin on the tallest row of stereocilia was dependent upon the isoform 2 of myosin 15 (short form)38. It is therefore probable that Gpsm2 and Gαi3 are part of a preferential complex with myosin 15 isoform 2 and whirlin.


Defective Gpsm2/G α i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
Gpsm2 mutations affect stereocilia elongation and neuronal outgrowth by regulating actin dynamics at tip complexes.Mechanistic model for Gpsm2-dependent stereocilia elongation and neuronal outgrowth. Gpsm2 accumulates at the tip complex of both structures via the myosin 15 motor protein in stereocilia and a comparable motor protein in filopodia. Gpsm2-dependent macromolecular protein complexes modulate actin dynamics at the tip of stereocilia (growing end) or the leading edge of the growth cone, participating respectively in the elongation and motility of the two structures. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5385604&req=5

f9: Gpsm2 mutations affect stereocilia elongation and neuronal outgrowth by regulating actin dynamics at tip complexes.Mechanistic model for Gpsm2-dependent stereocilia elongation and neuronal outgrowth. Gpsm2 accumulates at the tip complex of both structures via the myosin 15 motor protein in stereocilia and a comparable motor protein in filopodia. Gpsm2-dependent macromolecular protein complexes modulate actin dynamics at the tip of stereocilia (growing end) or the leading edge of the growth cone, participating respectively in the elongation and motility of the two structures. See text for details.
Mentions: Myosin 15 is the molecular motor responsible for delivering whirlin and Eps8 to the tips of actin-rich stereocilia and this ternary complex is required for elongation of nascent stereocilia. Our results show that myosin 15 and whirlin are also required for trafficking Gpsm2 and Gαi3, two new members of the stereocilia tip complex, an electron-dense structure believed to contain proteins that regulate actin polymerization (Fig. 9). Accordingly, when myosin 15 is non-functional, Gpsm2 and Gαi3 (this study), as well as whirlin17 and Eps8 (refs 19, 22) are all absent from the stereocilia tips. On the other hand, when Whrn, Gpsm2 or Gnai3 are mutated, myosin 15 still accumulates at the tips of short abnormal stereocilia. The failure of Whrn, Gpsm2 and Gnai3 cKOs stereocilia to elongate despite the localization of myosin 15, suggests that these proteins assemble in a macromolecular complex (including Eps8) to regulate actin polymerization at the stereocilia tips. Interestingly, it was recently shown that the distribution of whirlin on the tallest row of stereocilia was dependent upon the isoform 2 of myosin 15 (short form)38. It is therefore probable that Gpsm2 and Gαi3 are part of a preferential complex with myosin 15 isoform 2 and whirlin.

View Article: PubMed Central - PubMed

ABSTRACT

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

No MeSH data available.