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Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain

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Abstract

Dendritic arborization and axon outgrowth are critical steps in the establishment of neural connectivity in the developing brain. Changes in the connectivity underlie cognitive dysfunction in neurodevelopmental disorders. However, molecules and associated mechanisms that play important roles in dendritic and axon outgrowth in the brain are only partially understood. Here, we show that microtubule-actin crosslinking factor 1 (MACF1) regulates dendritic arborization and axon outgrowth of developing pyramidal neurons by arranging cytoskeleton components and mediating GSK-3 signaling. MACF1 deletion using conditional mutant mice and in utero gene transfer in the developing brain markedly decreased dendritic branching of cortical and hippocampal pyramidal neurons. MACF1-deficient neurons showed reduced density and aberrant morphology of dendritic spines. Also, loss of MACF1 impaired the elongation of callosal axons in the brain. Actin and microtubule arrangement appeared abnormal in MACF1-deficient neurites. Finally, we found that GSK-3 is associated with MACF1-controlled dendritic differentiation. Our findings demonstrate a novel role for MACF1 in neurite differentiation that is critical to the creation of neuronal connectivity in the developing brain.

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References

  1. Arimura N, Kaibuchi K (2007) Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci 8(3):194–205. doi:10.1038/nrn2056

    Article  CAS  PubMed  Google Scholar 

  2. Craig AM, Banker G (1994) Neuronal polarity. Annu Rev Neurosci 17:267–310. doi:10.1146/annurev.ne.17.030194.001411

    Article  CAS  PubMed  Google Scholar 

  3. Witte H, Bradke F (2008) The role of the cytoskeleton during neuronal polarization. Curr Opin Neurobiol 18(5):479–487. doi:10.1016/j.conb.2008.09.019

    Article  CAS  PubMed  Google Scholar 

  4. Bellon A (2007) New genes associated with schizophrenia in neurite formation: a review of cell culture experiments. Mol Psychiatry 12(7):620–629. doi:10.1038/sj.mp.4001985

    Article  CAS  PubMed  Google Scholar 

  5. Jan YN, Jan LY (2010) Branching out: mechanisms of dendritic arborization. Nat Rev Neurosci 11(5):316–328. doi:10.1038/nrn2836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kaufmann WE, Moser HW (2000) Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 10(10):981–991

    Article  CAS  PubMed  Google Scholar 

  7. Pardo CA, Eberhart CG (2007) The neurobiology of autism. Brain Pathol 17(4):434–447. doi:10.1111/j.1750-3639.2007.00102.x

    Article  CAS  PubMed  Google Scholar 

  8. Hur EM, Saijilafu ZFQ (2012) Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration. Trends Neurosci 35(3):164–174. doi:10.1016/j.tins.2011.11.002

    Article  CAS  PubMed  Google Scholar 

  9. Geraldo S, Gordon-Weeks PR (2009) Cytoskeletal dynamics in growth-cone steering. J Cell Sci 122(Pt 20):3595–3604. doi:10.1242/jcs.042309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Siegrist SE, Doe CQ (2007) Microtubule-induced cortical cell polarity. Genes Dev 21(5):483–496. doi:10.1101/gad.1511207

    Article  CAS  PubMed  Google Scholar 

  11. Fuchs E, Karakesisoglou I (2001) Bridging cytoskeletal intersections. Genes Dev 15(1):1–14

    Article  CAS  PubMed  Google Scholar 

  12. Jefferson JJ, Leung CL, Liem RK (2004) Plakins: goliaths that link cell junctions and the cytoskeleton. Nat Rev Mol Cell Biol 5(7):542–553. doi:10.1038/nrm1425

    Article  CAS  PubMed  Google Scholar 

  13. Kodama A, Karakesisoglou I, Wong E, Vaezi A, Fuchs E (2003) ACF7: an essential integrator of microtubule dynamics. Cell 115(3):343–354

    Article  CAS  PubMed  Google Scholar 

  14. Lin CM, Chen HJ, Leung CL, Parry DA, Liem RK (2005) Microtubule actin crosslinking factor 1b: a novel plakin that localizes to the Golgi complex. J Cell Sci 118(Pt 16):3727–3738. doi:10.1242/jcs.02510

    Article  CAS  PubMed  Google Scholar 

  15. Leung CL, Sun D, Zheng M, Knowles DR, Liem RK (1999) Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. J Cell Biol 147(6):1275–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun D, Leung CL, Liem RK (2001) Characterization of the microtubule binding domain of microtubule actin crosslinking factor (MACF): identification of a novel group of microtubule associated proteins. J Cell Sci 114(Pt 1):161–172

    CAS  PubMed  Google Scholar 

  17. Suozzi KC, Wu X, Fuchs E (2012) Spectraplakins: master orchestrators of cytoskeletal dynamics. J Cell Biol 197(4):465–475. doi:10.1083/jcb.201112034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen HJ, Lin CM, Lin CS, Perez-Olle R, Leung CL, Liem RK (2006) The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway. Genes Dev 20(14):1933–1945. doi:10.1101/gad.1411206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao FB, Brenman JE, Jan LY, Jan YN (1999) Genes regulating dendritic outgrowth, branching, and routing in Drosophila. Genes Dev 13(19):2549–2561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee S, Harris KL, Whitington PM, Kolodziej PA (2000) Short stop is allelic to kakapo, and encodes rod-like cytoskeletal-associated proteins required for axon extension. J Neurosci 20(3):1096–1108

    CAS  PubMed  Google Scholar 

  21. Prokop A, Uhler J, Roote J, Bate M (1998) The kakapo mutation affects terminal arborization and central dendritic sprouting of drosophila motorneurons. J Cell Biol 143(5):1283–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Reuter JE, Nardine TM, Penton A, Billuart P, Scott EK, Usui T, Uemura T, Luo L (2003) A mosaic genetic screen for genes necessary for drosophila mushroom body neuronal morphogenesis. Development 130(6):1203–1213

    Article  CAS  PubMed  Google Scholar 

  23. Sanchez-Soriano N, Travis M, Dajas-Bailador F, Goncalves-Pimentel C, Whitmarsh AJ, Prokop A (2009) Mouse ACF7 and drosophila short stop modulate filopodia formation and microtubule organisation during neuronal growth. J Cell Sci 122(Pt 14):2534–2542. doi:10.1242/jcs.046268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ka M, Jung EM, Mueller U, Kim WY (2014) MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling. Dev Biol 395(1):4–18. doi:10.1016/j.ydbio.2014.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E (2011) Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta. Cell 144(3):341–352. doi:10.1016/j.cell.2010.12.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jiang H, Guo W, Liang X, Rao Y (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120(1):123–135. doi:10.1016/j.cell.2004.12.033

    CAS  PubMed  Google Scholar 

  27. Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120(1):137–149. doi:10.1016/j.cell.2004.11.012

    Article  CAS  PubMed  Google Scholar 

  28. Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD (2004) NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron 42(6):897–912. doi:10.1016/j.neuron.2004.05.011

    Article  CAS  PubMed  Google Scholar 

  29. Kim WY, Zhou FQ, Zhou J, Yokota Y, Wang YM, Yoshimura T, Kaibuchi K, Woodgett JR (2006) Essential roles for GSK-3s and GSK-3-primed substrates in neurotrophin-induced and hippocampal axon growth. Neuron 52(6):981–996. doi:10.1016/j.neuron.2006.10.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Franco SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Muller U (2011) Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. Neuron 69(3):482–497. doi:10.1016/j.neuron.2011.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW (1998) The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development 125(12):2315–2325

    CAS  PubMed  Google Scholar 

  32. Grove EA, Tole S (1999) Patterning events and specification signals in the developing hippocampus. Cereb Cortex 9(6):551–561

    Article  CAS  PubMed  Google Scholar 

  33. Mangale VS, Hirokawa KE, Satyaki PR, Gokulchandran N, Chikbire S, Subramanian L, Shetty AS, Martynoga B et al (2008) Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate. Science 319(5861):304–309. doi:10.1126/science.1151695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Monuki ES, Porter FD, Walsh CA (2001) Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 32(4):591–604

    Article  CAS  PubMed  Google Scholar 

  35. Cingolani LA, Goda Y (2008) Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9(5):344–356. doi:10.1038/nrn2373

    Article  CAS  PubMed  Google Scholar 

  36. Frost NA, Shroff H, Kong H, Betzig E, Blanpied TA (2010) Single-molecule discrimination of discrete perisynaptic and distributed sites of actin filament assembly within dendritic spines. Neuron 67(1):86–99. doi:10.1016/j.neuron.2010.05.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Harnett MT, Makara JK, Spruston N, Kath WL, Magee JC (2012) Synaptic amplification by dendritic spines enhances input cooperativity. Nature 491(7425):599–602. doi:10.1038/nature11554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sanders J, Cowansage K, Baumgartel K, Mayford M (2012) Elimination of dendritic spines with long-term memory is specific to active circuits. J Neurosci 32(36):12570–12578. doi:10.1523/JNEUROSCI.1131-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Courchet J, Lewis TL Jr, Lee S, Courchet V, Liou DY, Aizawa S, Polleux F (2013) Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell 153(7):1510–1525. doi:10.1016/j.cell.2013.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ivy GO, Killackey HP (1981) The ontogeny of the distribution of callosal projection neurons in the rat parietal cortex. J Comp Neurol 195(3):367–389. doi:10.1002/cne.901950302

    Article  CAS  PubMed  Google Scholar 

  41. Wang CL, Zhang L, Zhou Y, Zhou J, Yang XJ, Duan SM, Xiong ZQ, Ding YQ (2007) Activity-dependent development of callosal projections in the somatosensory cortex. J Neurosci 27(42):11334–11342. doi:10.1523/JNEUROSCI.3380-07.2007

    Article  CAS  PubMed  Google Scholar 

  42. Llano I, Tan YP, Caputo C (1997) Spatial heterogeneity of intracellular Ca2+ signals in axons of basket cells from rat cerebellar slices. J Physiol 502(Pt 3):509–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jones SB, Lu HY, Lu Q (2004) Abl tyrosine kinase promotes dendrogenesis by inducing actin cytoskeletal rearrangements in cooperation with Rho family small GTPases in hippocampal neurons. J Neurosci 24(39):8510–8521. doi:10.1523/JNEUROSCI.1264-04.2004

    Article  CAS  PubMed  Google Scholar 

  44. Mattila PK, Lappalainen P (2008) Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9(6):446–454. doi:10.1038/nrm2406

    Article  CAS  PubMed  Google Scholar 

  45. Goebbels S, Bormuth I, Bode U, Hermanson O, Schwab MH, Nave KA (2006) Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice. Genesis 44(12):611–621. doi:10.1002/dvg.20256

    Article  CAS  PubMed  Google Scholar 

  46. Gregory SL, Brown NH (1998) kakapo, a gene required for adhesion between and within cell layers in Drosophila, encodes a large cytoskeletal linker protein related to plectin and dystrophin. J Cell Biol 143(5):1271–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kolodziej PA, Jan LY, Jan YN (1995) Mutations that affect the length, fasciculation, or ventral orientation of specific sensory axons in the Drosophila embryo. Neuron 15(2):273–286

    Article  CAS  PubMed  Google Scholar 

  48. Strumpf D, Volk T (1998) Kakapo, a novel cytoskeletal-associated protein is essential for the restricted localization of the neuregulin-like factor, vein, at the muscle-tendon junction site. J Cell Biol 143(5):1259–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Goryunov D, He CZ, Lin CS, Leung CL, Liem RK (2010) Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental defects in the mouse brain. Mol Cell Neurosci 44(1):1–14. doi:10.1016/j.mcn.2010.01.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang X, Qiu R, Tsark W, Lu Q (2007) Rapid promoter analysis in developing mouse brain and genetic labeling of young neurons by doublecortin-DsRed-express. J Neurosci Res 85(16):3567–3573. doi:10.1002/jnr.21440

    Article  CAS  PubMed  Google Scholar 

  51. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ et al (2007) Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 12(1):74–86. doi:10.1038/sj.mp.4001880

    Article  CAS  PubMed  Google Scholar 

  52. Bourne JN, Harris KM (2008) Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci 31:47–67. doi:10.1146/annurev.neuro.31.060407.125646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Harris KM, Kater SB (1994) Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 17:341–371. doi:10.1146/annurev.ne.17.030194.002013

    Article  CAS  PubMed  Google Scholar 

  54. Chapleau CA, Larimore JL, Theibert A, Pozzo-Miller L (2009) Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. J Neurodev Disord 1(3):185–196. doi:10.1007/s11689-009-9027-6

    Article  PubMed  PubMed Central  Google Scholar 

  55. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14(3):285–293. doi:10.1038/nn.2741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Marin O, Valiente M, Ge X, Tsai LH (2010) Guiding neuronal cell migrations. Cold Spring Harb Perspect Biol 2(2):a001834. doi:10.1101/cshperspect.a001834

    Article  PubMed  PubMed Central  Google Scholar 

  57. Li R, Gundersen GG (2008) Beyond polymer polarity: how the cytoskeleton builds a polarized cell. Nat Rev Mol Cell Biol 9(11):860–873. doi:10.1038/nrm2522

    Article  CAS  PubMed  Google Scholar 

  58. Polleux F, Snider W (2010) Initiating and growing an axon. Cold Spring Harb Perspect Biol 2(4):a001925. doi:10.1101/cshperspect.a001925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roper K, Gregory SL, Brown NH (2002) The ‘spectraplakins’: cytoskeletal giants with characteristics of both spectrin and plakin families. J Cell Sci 115(Pt 22):4215–4225

    Article  CAS  PubMed  Google Scholar 

  60. Gupta T, Marlow FL, Ferriola D, Mackiewicz K, Dapprich J, Monos D, Mullins MC (2010) Microtubule actin crosslinking factor 1 regulates the Balbiani body and animal-vegetal polarity of the zebrafish oocyte. PLoS Genet 6(8):e1001073. doi:10.1371/journal.pgen.1001073

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhou FQ, Snider WD (2005) Cell biology. GSK-3beta and microtubule assembly in axons. Science 308(5719):211–214

    Article  CAS  PubMed  Google Scholar 

  62. Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11(8):539–551. doi:10.1038/nrn2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lim CS, Walikonis RS (2008) Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal 20(5):825–835. doi:10.1016/j.cellsig.2007.12.013

    Article  CAS  PubMed  Google Scholar 

  64. Sutherland C (2011) What are the bona fide GSK3 substrates? Int J Alzheimers Dis 2011:505607. doi:10.4061/2011/505607

    PubMed  PubMed Central  Google Scholar 

  65. Kim WY, Fayazi Z, Bao X, Higgins D, Kazemi-Esfarjani P (2005) Evidence for sequestration of polyglutamine inclusions by Drosophila myeloid leukemia factor. Mol Cell Neurosci 29(4):536–544. doi:10.1016/j.mcn.2005.04.005

    Article  CAS  PubMed  Google Scholar 

  66. Ka M, Condorelli G, Woodgett JR, Kim WY (2014) mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development 141(21):4076–4086. doi:10.1242/dev.108282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, Snider WD (2009) GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 12(11):1390–1397. doi:10.1038/nn.2408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kim WY, Horbinski C, Sigurdson W, Higgins D (2004) Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons. J Neurochem 91(5):1044–1056. doi:10.1111/j.1471-4159.2004.02788.x

    Article  CAS  PubMed  Google Scholar 

  69. Kim WY, Gonsiorek EA, Barnhart C, Davare MA, Engebose AJ, Lauridsen H, Bruun D, Lesiak A et al (2009) Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation. J Neurochem 108(4):1057–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Dr. Robert Norgren for valuable comments on the manuscript. Research reported in this publication was supported by an award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS091220, an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under award number P20GM103471, a grant from NE DHHS (Stem Cell 2012-05), and a grant from Alzheimer’s Association (NIRP-12-258440) to WYK.

Author Contribution

M.K. and W.K. conceived, designed, performed and analyzed the study. W.K. supervised the work. M.K. and W.K. wrote the paper.

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  1. Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Minhan Ka & Woo-Yang Kim

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  1. Minhan Ka
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Correspondence to Woo-Yang Kim.

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Supplemental Fig. 1

MACF1 deletion effect on dendrites in cultured neurons (a) Cortical neurons from control (MACF1 loxP/+; Nex-cre) and MACF1 loxP/loxP; Nex-cre brains at E14.5 were cultured for 3 days. Dendrites were visualized by MAP2 immunostaining. (b) The number and the length of dendrites were quantified. n = 75 cells from 3 independent cultures using 3 mice for each condition. Statistical significance was determined by two-tailed Student’s t-test. ***p < 0.001 (PDF 82 kb).

Supplemental Fig. 2

MACF1 deletion effect on callosal axon projection Callosal axons from P0 control (MACF1 loxP/+; Nex-cre) and MACF1 loxP/loxP; Nex-cre brains were examined. Brains were immunostained with an L1 antibody. Reduced intensity of L1 fluorescence was shown in MACF1 loxP/loxP; Nex-cre brains compared with controls (PDF 212 kb).

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Ka, M., Kim, WY. Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain. Mol Neurobiol 53, 6018–6032 (2016). https://doi.org/10.1007/s12035-015-9508-4

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