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International Conference on Myasthenia

Paris, December 1-2, 2009. International Conference on Myasthenia. Dok-7, MuSK, and the development of the neuromuscular junction. Yuji Yamanashi Dept. Genetics Inst. Medical Science University of Tokyo. Paris, December 1-2, 2009. International Conference on Myasthenia.

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International Conference on Myasthenia

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  1. Paris, December 1-2, 2009 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Yuji Yamanashi Dept. Genetics Inst. Medical Science University of Tokyo

  2. Paris, December 1-2, 2009 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction • The receptor protein-tyrosine kinase MuSK controls where the NMJ develops. • The cytoplasmic, adaptor-like protein Dok-7 is an essential activator of MuSK

  3. The receptor protein-tyrosine kinase (PTK) MuSK Ig-like domains (Agrin response) Frizzled-like cystein-rich domain （Wnt response ?） PTK domain (catalytic domain) (Jennings et al., PNAS.90: 2895-2899, 1993) (Zhang et al., Develop. Cell.16: 325-327, 1993) • MuSK is essential for the development of NMJs • MuSK controls where NMJs form in myotubes (DeChiara et al., Cell 85: 501-512, 1996) (Kim et al., Nat. Neurosci.11: 19-27, 2008)

  4. AChRs form postsynaptic clusters in the central region of the muscle Myotube AChR Nerve Wild-type AChRs form postsynaptic clusters (red) in the central region of myotubes. AChR cluster （postsynaptic region） ( E18.5 Diaphragm ) MuSK is expressed in the central region of myotubes.

  5. MuSK controls where the NMJs form Myotube AChR Nerve Wild-type AChRs form postsynaptic clusters in the central region of myotubes. MuSK Tg (overexpression in the muscle) Uniformly overexpressed MuSK induces scattered AChR cluster formation; and NMJs are also scattered. ( E18.5 Diaphragm ) (Kim et al., Nat. Neurosci.11: 19-27, 2008) AChR cluster （postsynaptic region）

  6. MuSK controls where the NMJs form Myotube AChR Nerve Wild-type AChRs form postsynaptic clusters (red) in the central region of myotubes. MuSK Tg (overexpression in the muscle) Uniformly overexpressed MuSK induces scattered AChR cluster formation; and NMJs are also scattered. MuSK KO MuSK-KO mice form no AChR cluster ( Diaphragm ) AChR cluster （postsynaptic region） (Lin et al., Nature410: 1057-1064, 2001) (Kim et al., Nat. Neurosci.11: 19-27, 2008)

  7. . . . . . . Neural Agrin activates MuSK via LRP4 coreceptor. (Kim et al., Cell135: 334-342, 2008) (Zhang et al., Neuron60: 285-297, 2008) LRP4 motor nerve motor nerve terminal Motor nerve terminal Agrin Agrin Agrin Agrin LRP4 LRP4 LRP4 AChR cluster Rapsyn MuSK AChR Myotube Myotube

  8. . . . . . . Nerve/Agrin-independent but MuSK-dependent AChR clustering Nerve Nerve AChR AChR WT Agrin KO HB9 KO MuSK KO (E14.5 Diaphragm) LRP4 ( Lin et al, Nature 410:1057-1064, 2001) motor nerve motor nerve terminal Motor nerve terminal Agrin Agrin Agrin Agrin LRP4 LRP4 LRP4 AChR cluster Rapsyn MuSK AChR Myotube Myotube

  9. . . . . . . Nerve/Agrin-independent but MuSK-dependent AChR clustering Nerve Nerve AChR AChR WT Agrin KO HB9 KO MuSK KO (E14.5 Diaphragm) LRP4 ( Lin et al, Nature 410:1057-1064, 2001) motor nerve Nerve/Agrin-independent, probably muscle-intrinsic element(s) may exist to activate MuSK Agrin Agrin LRP4 LRP4 LRP4 ? （　　　） AChR cluster Rapsyn MuSK AChR Myotube Myotube

  10. . . . . . . Nerve/Agrin-independent but MuSK-dependent AChR clustering Nerve Nerve AChR AChR WT Agrin KO HB9 KO MuSK KO (E14.5 Diaphragm) LRP4 ( Lin et al, Nature 410:1057-1064, 2001) motor nerve Nerve/Agrin-independent, probably muscle-intrinsic element(s) may activate MuSK Agrin Agrin LRP4 LRP4 LRP4 Dok-7 AChR cluster Rapsyn MuSK AChR Myotube Myotube

  11. Dok-family Y: SH2 binding/target motif Y Y Y Y Y Y Y Y Y Y Dok-1(62kD) PH PTB (100%) (100%) Y Y Y Y Y Y High expression in hematopoietic cells Dok-2(56kD) PH PTB ( 40%) ( 50%) Y Y Y Y Dok-3(58kD) PH PTB ( 50%) ( 40%) Y Y Y Y Y Dok-4(41kD) PH PTB Y Y Y ( - - -) ( 30%) PH PTB High expression in non-hematopoietic cells Dok-5(36kD) Y Y Y Y ( - - -) ( 35%) PH PTB Dok-6(36kD) PH PTB ( - - -) ( 35%) Y Y High expression in muscles Dok-7 (55kD) ( - - -) ( 20%)

  12. SCFR M-CSFR GM-CSFR IL-3R TLR4 BCR Dok-1/2 Dok-1/2 Receptor PTKs Non-Receptor PTKs Ras-Erk (Proliferation & Cytokine Production) Yamanashi & Baltimore, Cell, 1997 Yamanashi et al., Genes Dev., 2000 Yasuda et al., J. Exp. Med., 2004, Shinohara et al., J. Exp. Med., 2005

  13. Dok-family proteins Y: SH2 binding/target motif Y Y Y Y Y Y Y Y Y Y Dok-1(62kD) PH PTB (100%) (100%) Y Y Y Y Y Y High expression in hematopoietic cells Dok-2(56kD) PH PTB ( 40%) ( 50%) Y Y Y Y Dok-3(58kD) PH PTB ( 50%) ( 40%) Y Y Y Y Y Dok-4(41kD) PH PTB Y Y Y ( - - -) ( 30%) PH PTB High expression in non-hematopoietic cells Dok-5(36kD) Y Y Y Y ( - - -) ( 35%) PH PTB Dok-6(36kD) PH PTB ( - - -) ( 35%) Y Y High expression in muscles Dok-7 (55kD) ( - - -) ( 20%) （Okada et al., Science, 2006）

  14. Postsynaptic localization of Dok-7 at Neuromuscular Junction (NMJ) gastrocnemius Presynaptic vesicle (+ACh: acetylcholine) AChR (ACh receptor) cluster myotube Dok-7 AChR Merge NMJ (Neuromuscular Junction) (-Dok-7 Ab) (bungarotoxin) motor nerve NMJ myotube MuSK AChR (Apel et al., Neuron, 1997)

  15. . . . . . . Postsynaptic localization of Dok-7 at Neuromuscular Junction (NMJ) gastrocnemius Presynaptic vesicle (+ACh: acetylcholine) AChR (ACh receptor) cluster myotube Dok-7 AChR Merge NMJ (Neuromuscular Junction) (-Dok-7 Ab) (bungarotoxin) LRP4 Agrin-MuSK -Dok-7 signaling ? motor nerve motor nerve terminal Motor nerve terminal Agrin Agrin Agrin Agrin LRP4 LRP4 LRP4 Dok-7 Dok-7 PH PH PH ? ? PTB PTB AChR cluster Rapsyn MuSK Y Y AChR Y Y Myotube Myotube

  16. pY Dok-7 induces MuSK activation and AChR clustering in myotubes / Dok-7 AChR AChR P MuSK pY MuSK  pY-AChR1 pY AChR-PD Dok-7 myotubes WCL Tubulin ( ) （C2C12） Dok-7 myotubes ( AChR : ACh Receptor ) IP ： Immunoprecipitation IB ： Immunoblotting PD： Pull-down WCL： Whole cell lysates apY： anti-phosphotyrosine

  17. pY Dok-7 induces MuSK activation and AChR clustering in myotubes / Dok-7 AChR AChR P MuSK pY MuSK  pY-AChR1 pY AChR-PD Dok-7 myotubes WCL Tubulin ( ) （C2C12） Dok-7 LRP4 Dok-7 can activate MuSK independently of Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  18. . . . . . . Nerve/Agrin-independent but MuSK-dependent AChR clustering Nerve Nerve AChR AChR WT Agrin KO HB9 KO MuSK KO (E14.5 Diaphragm) LRP4 ( Lin et al, Nature 410:1057-1064, 2001) motor nerve Nerve/Agrin-independent, probably muscle-intrinsic element(s) may activate MuSK Agrin Agrin LRP4 LRP4 LRP4 Dok-7 AChR cluster Rapsyn MuSK AChR Myotube Myotube

  19. Is Dok-7 a muscle-intrinsic activator of MuSK in vivo ? LRP4 Dok-7 can activate MuSK independently of Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  20. . . . . . . Merge Merge Nerve AChR Nerve AChR WT WT Dok-7 KO Dok-7 KO (E14.5 diaphragm) (E18.5 diaphragm) LRP4 E14.5 motor nerve Dok-7 is essential for AChR clustering and NMJ formation in vivo E14.5 Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  21. 100 75 50 . . . . . . E18.5 WT Tg Dok-7-EGFP Dok-7 IP: Dok-7 IB: Dok-7 LRP4 motor nerve Overexpression of Dok-7 in vivo Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  22. 100 75 50 . . . . . . Merge Nerve AChR E18.5 WT Tg WT Dok-7-EGFP Dok-7 Tg Dok-7 IP: Dok-7 IB: Dok-7 E18.5 Diaphragm LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Overexpression of Dok-7 in vivo facilitates AChR cluster formation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  23. . . . . . . Merge Nerve AChR 100 WT 80 60 Myofibers（％） WT 40 Dok-7 Tg 20 Dok-7 Tg 0 1 2 3 4 5 6 7 8 9 AChR clusters per myofiber E18.5 Diaphragm LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Overexpression of Dok-7 in vivo facilitates AChR cluster formation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  24. . . . . . . Merge Nerve AChR AChR cluster(s) on a myotube WT WT Dok-7 Tg Dok-7 Tg E18.5 Diaphragm LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Overexpression of Dok-7 in vivo facilitates AChR cluster formation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  25. . . . . . . Dok-7 induces NMJ formation in vivo AChR cluster(s) on a myotube E18.5 200 ** **P < 0.001 WT 150 Number of NMJs（％ of WT） 100 50 Dok-7 Tg 0 WT Dok-7 Tg LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Overexpression of Dok-7 in vivo facilitates NMJ formation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  26. . . . . . . Dok-7 activates MuSK in vivo 100 100 IP: MuSK pY-MuSK AChR-PD (Btx) pY-AChR WT Tg 160 160 * *P < 0.05 Tg - - - + pY-MuSK **P < 0.003 140 140 Dok-7 +/+ -/- -/- +/+ 120 120 ** IB: PY 100 100 50 pY-AChR 80 80 Relative intensity Relative intensity MuSK 60 60 IB: PY 40 40 IB: MuSK 50 AChR 20 20 0 0 IB: AChR (b1) WT Dok-7 Tg WT Dok-7 Tg LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Dok-7 is an essential activator of MuSK Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  27. . . . . . . Nerve AChR Nerve AChR WT Agrin KO HB9 KO MuSK KO (E14.5 diaphragm) LRP4 ( Lin et al, Nature 410:1057-1064, 2001) motor nerve Dok-7 is an essential activator of MuSK Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  28. . . . . . . Merge Merge Nerve AChR Nerve AChR WT WT Dok-7 KO Dok-7 KO (E14.5 diaphragm) (E18.5 diaphragm) LRP4 E14.5 motor nerve Why Agrin cannot induce AChR clustering in Dok-7 KO mice? E14.5 Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  29. . . . . . . Merge Merge Nerve AChR Nerve AChR WT WT Dok-7 KO Dok-7 KO (E14.5 diaphragm) (E18.5 diaphragm) LRP4 E14.5 motor nerve Dok-7 may be required for Agrin-mediated MuSK activation E14.5 Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  30. WT Dok-7 -/- Agrin 0 10 30 0 10 30 (min) 150 100 IP: MuSK IB: pY 150 100 LRP4 ( myotube ) IB: MuSK Dok-7 is required for Agrin-mediated MuSK activation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  31. Agrin (-) Agrin (+) WT Dok-7 -/- WT Agrin 0 10 30 0 10 30 (min) Dok-7-/- 150 Dok-7-/- + Dok-7 100 IP: MuSK IB: pY AChR 150 100 LRP4 ( myotube ) IB: MuSK ( Inoue et al. Science Signaling, 2009 ) Dok-7 is required for Agrin-mediated MuSK activation Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  32. . . . . . . Merge Nerve Nerve AChR AChR WT Agrin KO Dok-7 KO MuSK KO (E18.5 diaphragm) ( Lin et al, Nature 410:1057-1064, 2001) LRP4 motor nerve Dok-7 is a key muscle-intrinsic activator of MuSK Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  33. . . . . . . How does Dok-7 activate MuSK from the cytoplasmic compartment ? LRP4 motor nerve Dok-7 is a key muscle-intrinsic activator of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  34. . . . . . . How does Dok-7 activate MuSK from the cytoplasmic compartment ? LRP4 motor nerve Dok-7 is a key muscle-intrinsic activator of MuSK LRP4 LRP4 LRP4 ? PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  35. PH PTB Y Y The ectodmain of MuSK is dispensble for Dok-7-mediated activation Ig MuSK WT + + Dok-7 pY-MuSK pY-MuSK-Ig IB: pY MuSK-Ig Dok-7 WT MuSK-Ig Dok-7 may target the cytoplasmic portion of MuSK IB: myc (MuSK) IB: Dok-7 DOK-7 (293T cells) ( Inoue et al. Science Signaling, 2009 )

  36. PH PH PTB PTB Y Y Y Y The ectodmain and transmembrane region of MuSK are dispensble for Dok-7-mediated activation Cyt Ig MuSK WT + + + Dok-7 pY-MuSK pY-MuSK-Ig IB: pY Dok-7 MuSK-Cyt pY-MuSK-Cyt WT MuSK-Ig IB: myc (MuSK) MuSK-Cyt IB: Dok-7 DOK-7 (293T cells) MuSK-Ig Dok-7 ( Inoue et al. Science Signaling, 2009 )

  37. PH PTB Y Y The ectodmain and transmembrane region of MuSK are dispensble for Dok-7-mediated activation Cyt Ext MuSK WT + + + Dok-7 pY-MuSK pY-MuSK-Ig IB: pY Dok-7 MuSK-Cyt pY-MuSK-Cyt LRP4 Dok-7 targets the cytoplasmic portion of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  38. Does Dok-7 directly activate the cytoplasmic portion of MuSK? LRP4 Dok-7 targets the cytoplasmic portion of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  39. PH PTB Y Y MuSK-cyt Dok-7 250 150 100 75 Dok-7 50 37 MuSK-Cyt 25 (kDa) (CBB) LRP4 Dok-7 targets the cytoplasmic portion of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  40. PH PTB Y Y Dok-7 MuSK-cyt + Dok-7 MuSK-cyt 0 5 15 30 60 120 (min) 0 5 15 30 60 120 75 pY-Dok-7-His 50 37 pY-MuSK-cyt MuSK-Cyt pY: phosphotyrosine LRP4 ( Inoue et al. Science Signaling, 2009 ) 25 IB: pY IB: pY Dok-7 directly activates the cytoplasmic portion of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  41. PH PTB Y Y Dok-7 MuSK-cyt + Dok-7 MuSK-cyt + Dok-7DN 0 5 15 30 60 120 (min) pY-MuSK-cyt MuSK-cyt 0 5 15 30 60 120 (min) 0 5 15 30 60 120 75 pY-Dok-7-His 50 IB: pY 37 pY-MuSK-cyt MuSK-Cyt pY: phosphotyrosine LRP4 ( Inoue et al. Science Signaling, 2009 ) 25 IB: pY IB: pY Dok-7 directly activates the cytoplasmic portion of MuSK LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  42. ＊ . . . . . . Myotube AChR Merge Nerve WT WT Dok-7 Tg Dok-7 Tg Overexpression of Dok7 AChR cluster （postsynaptic region） E18.5 Diaphragm LRP4 ( Inoue et al. Science Signaling, 2009 ) motor nerve Why uniform overexpression of Dok-7 facilitates centrally formation of the NMJ ? Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  43. ＊ Myotube AChR Merge Nerve WT WT Dok-7 Tg Dok-7 Tg Overexpression of Dok7 AChR cluster （postsynaptic region） E18.5 Diaphragm ( Inoue et al. Science Signaling, 2009 ) Is MuSK expressed in the central region of Dok-7 Tg muscle?

  44. Dok-7 is essential for mid-muscle expression of MuSK and AChR Dok-7 -/- WT Dok-7Tg Dok-7 -/- WT Dok-7Tg E14.5 E14.5 E18.5 E18.5 in situ hybrid. (Diaphragm) MuSK AChRa MuSK is expressed in the central region of Dok-7 Tg muscle, and Dok-7 is required for the centrally restricted expression of MuSK and AChR

  45. Dok-7 is essential for mid-muscle expression of MuSK and AChR Dok-7 -/- WT Dok-7Tg Dok-7 -/- WT Dok-7Tg E14.5 E14.5 E18.5 E18.5 in situ hybrid. (Diaphragm) MuSK AChRa Immunostaining (Diaphragm) scale bar: 100 mm

  46. Dok-7 is essential for mid-muscle expression of MuSK and AChR Dok-7 -/- WT Dok-7Tg Dok-7 -/- WT Dok-7Tg E14.5 E14.5 E18.5 E18.5 in situ hybrid. (Diaphragm) MuSK AChRa LRP4 Dok-7 regulates the mid-muscle NMJ formation by controlling MuSK activity, expression pattern, and responsiveness to Agrin. LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  47. A simplified model of Dok-7-MuSK-Agrin signaling in the NMJ formation Ⅰ Ⅲ Motor nerve Agrin ACh Agrin ACh MuSK MuSK LRP4 Dok-7 Dok-7 (myotube) (myotube) Dok-7 is expressed in the central region of skeletal muscle, where it activates MuSK and induces MuSK’s mid-muscle pattern formation. ACh disperses non-innervated AChR clusters but the local mediator Agrin fully activates Dok-7-primed/activated MuSK and counteracts ACh. Ⅱ Ⅳ Motor nerve MuSK AChR ACh MuSK Dok-7 Rapsyn Dok-7 (myotube) Activated MuSK induces postsynaptic specialization in the central region of muscle independently of nerve and Agrin. (myotube) Dok-7-MuSK-Agrin triad signaling promotes and reinforces NMJ formation.

  48. . . . . . . Nerve Merge AChR Nerve Merge AChR WT WT Dok-7 -/- Dok-7 -/- + Dok-7 Tg Dok-7 Tg ( Inoue et al. Science Signaling, 2009 ) E14.5 Diaphragm (unpublished) LRP4 motor nerve Dok-7 Tg rescues NMJs in Dok KO mice Agrin Agrin LRP4 LRP4 LRP4 Dok-7 PH PH PH PH PTB PTB PTB Dok-7 AChR cluster Rapsyn Y MuSK Y Y AChR Y Y Y Myotube Myotube

  49. Paris, December 1-2, 2009 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction • Dok-7 is an essential, muscle-intrinsic activator of MuSK, in NMJ development • Enhanced Dok-7 signaling may ameliorate DOK7 and MuSK-related myasthenia

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