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Gene Review

Gap43  -  growth associated protein 43

Mus musculus

Synonyms: Axonal membrane protein GAP-43, B-50, Basp2, Calmodulin-binding protein P-57, GAP-43, ...
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Background of Gap43

Although several different laboratories studying the same protein, now called GAP-43, used different names, the protein was initially designated F1, then B-50, then GAP-43, pp46, and finally neuromodulin (Benowitz, L.I. and Routtenberg, A. (1987) A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity. Trends in Neurosciences 10:527-532.). In each case, a function was assigned to the molecule. F1 was localized to synapses, and was increased in its phosphorylation one day after learning. However, F1 was ''not'' cAMP kinase dependent. B-50 was regulated by the pituitary peptide ACTH and is associated with the grooming of behavior. In the case of GAP-43, it was designated as a growth-associated protein because its synthesis was upregulated during axonal regeneration. Pp46 was strongly concentrated in neuronal growth cones and was thus postulated to play an important role in brain development. In the case of neuromodulin, it was shown to bind calmodulin avidly.


Disease relevance of Gap43


Psychiatry related information on Gap43


High impact information on Gap43

  • The results establish GAP-43 as an intrinsic presynaptic determinant for neurite outgrowth and plasticity [9].
  • Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43 [10].
  • In control mice, these nerve fibers did not express GAP-43, and did not sprout spontaneously [9].
  • Thus, the GAP-43 protein is not essential for axonal outgrowth or growth cone formation per se, but is required at certain decision points, such as the optic chiasm [10].
  • GAP-43-deficient retinal axons remain trapped in the chiasm for 6 days, unable to navigate past this midline decision point [10].

Chemical compound and disease context of Gap43


Biological context of Gap43

  • The map position of Gap43 indicates the presence, on mouse chromosome 16, of a significant-size conserved linkage group with human chromosome 3 [12].
  • The genetic map incorporates three new markers: D16Smh6, a random genomic clone; Pgk-1ps1, a phosphoglycerate kinase pseudogene; and the growth-associated protein Gap43 [12].
  • The results demonstrate that GAP-43 and L1 coexpressed in Purkinje cells can act synergistically to switch these regeneration-incompetent CNS neurons into a regeneration-competent phenotype and show that coexpression of these molecules is a key regulator of the regenerative ability of intrinsic CNS neurons in vivo [13].
  • Neuronal expression of growth-associated protein 43 (GAP-43) and the cell adhesion molecule L1 has been correlated with CNS axonal growth and regeneration, but it is not known whether expression of these molecules is necessary for axonal regeneration to occur [13].
  • B-50/GAP-43, a neural growth-associated phosphoprotein, is thought to play a role in neuronal plasticity and nerve fiber formation since it is expressed at high levels in developing and regenerating neurons and in growth cones [14].

Anatomical context of Gap43

  • Purkinje cells expressing GAP-43 or L1 showed minor enhancement of axonal sprouting [13].
  • We have taken advantage of the fact that Purkinje cells do not express GAP-43 or L1 in adult mammals or regenerate axons into peripheral nerve grafts to test the importance of these molecules for axonal regeneration in vivo [13].
  • These observations provide direct in vivo evidence for a role of B-50/GAP-43 in nerve fiber formation and in the determination of the morphology of axons [14].
  • These results indicate that MARCKS, neuromodulin, and other calmodulin-binding protein kinase C substrates exhibit distinct levels of expression in cultured neurotumor cell lines [15].
  • Moderate CCI increased GAP-43 levels at 24 and 48 h post-insult in the ipsilateral hippocampus relative to sham, non-injured animals [16].

Associations of Gap43 with chemical compounds


Physical interactions of Gap43


Regulatory relationships of Gap43

  • Newly formed neurons differentiate in the basal layers of the olfactory neuroepithelium and express B-50/GAP-43, a protein implicated in neurite outgrowth [23].
  • GAP-43 is an abundant intracellular growth cone protein that can serve as a PKC substrate and regulate calmodulin availability [24].
  • We found that among the members of the NeuroD subfamily, Nex1 promoted maximal activity of the GAP-43 promoter [25].
  • GAP43-expressing cells were located between these two NeuroD-positive layers [26].
  • Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant down-regulation of GAP-43 expression [27].
  • Using in vitro and in vivo experiments, we demonstrated that NFAT-3 regulates GAP-43, but unexpectedly, does not promote but represses the expression of GAP-43 in neurons and in the developing brain [28].

Other interactions of Gap43

  • Here, a defined subpopulation of nerve fibers increased in number during anagen and declined during catagen, accompanied by dynamic alterations in the expression of NCAM and GAP-43 [29].
  • The male map showed significant compression in the interval Smst to Gap43 [30].
  • In the present study, a unilateral cochleotomy was performed in adult mice to examine the relationship between the reemergence of GAP-43 and the expression pattern of nNOS [31].
  • Furthermore, the mRNA expression of alpha-Ca2+/calmodulin-dependent kinase II (alpha-CaMKII) was reduced in both the hippocampus and parietal cortex, whereas growth-associated protein 43 (GAP-43) mRNA expressions were induced in the corresponding regions [32].
  • The other markers included in this study were Prm-1, Gap43 and Sod-1 [33].

Analytical, diagnostic and therapeutic context of Gap43

  • GAP-43 and RC3 protein levels also were measured by Western blot [20].
  • Sequence analysis of human cDNAs coding for this protein shows that the human GAP-43 gene is highly homologous to the rat gene; this homology extends into the 3'-untranslated region [34].
  • Targeted overexpression of the neurite growth-associated protein B-50/GAP-43 in cerebellar Purkinje cells induces sprouting after axotomy but not axon regeneration into growth-permissive transplants [35].
  • Using quantitative in situ hybridization, we found that HuD overexpression led to selective increases in GAP-43 mRNA in hippocampal dentate granule cells and neurons in the lateral amygdala and layer V of the neorcortex [36].
  • We compared excitatory synaptic transmission between hippocampal pyramidal cells in dissociated hippocampal cell cultures and in area CA3 of hippocampal slice cultures derived from wild-type mice and mice with a genetic deletion of the presynaptic growth associated protein GAP-43 [37].


  1. Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice. Borges, K., McDermott, D.L., Dingledine, R. Exp. Neurol. (2004) [Pubmed]
  2. Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Bomze, H.M., Bulsara, K.R., Iskandar, B.J., Caroni, P., Skene, J.H. Nat. Neurosci. (2001) [Pubmed]
  3. Studies on the relationship of the B700 and B50 murine melanoma antigens. Hearing, V.J., Marchalonis, J.J., Gersten, D.M. J. Natl. Cancer Inst. (1986) [Pubmed]
  4. Long-term potentiation activates the GAP-43 promoter: selective participation of hippocampal mossy cells. Namgung, U., Matsuyama, S., Routtenberg, A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Expression of the Thy-1 glycoprotein gene by DNA-mediated gene transfer. Evans, G.A., Ingraham, H.A., Lewis, K., Cunningham, K., Seki, T., Moriuchi, T., Chang, H.C., Silver, J., Hyman, R. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  6. Hippocampal-dependent memory is impaired in heterozygous GAP-43 knockout mice. Rekart, J.L., Meiri, K., Routtenberg, A. Hippocampus. (2005) [Pubmed]
  7. Alterations of protein kinase C isozyme and substrate proteins in mouse brain after electroconvulsive seizures. Chen, C.C. Brain Res. (1994) [Pubmed]
  8. GAP-43 heterozygous mice show delayed barrel patterning, differentiation of radial glia, and downregulation of GAP-43. McIlvain, V., McCasland, J.S. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. (2006) [Pubmed]
  9. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Aigner, L., Arber, S., Kapfhammer, J.P., Laux, T., Schneider, C., Botteri, F., Brenner, H.R., Caroni, P. Cell (1995) [Pubmed]
  10. Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43. Strittmatter, S.M., Fankhauser, C., Huang, P.L., Mashimo, H., Fishman, M.C. Cell (1995) [Pubmed]
  11. Targeted disruption of GAP-43 in P19 embryonal carcinoma cells inhibits neuronal differentiation. As well as acquisition of the morphological phenotype. Mani, S., Schaefer, J., Meiri, K.F. Brain Res. (2000) [Pubmed]
  12. The multipoint genetic mapping of mouse chromosome 16. Irving, N.G., Hardy, J.A., Brown, S.D. Genomics (1991) [Pubmed]
  13. Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo. Zhang, Y., Bo, X., Schoepfer, R., Holtmaat, A.J., Verhaagen, J., Emson, P.C., Lieberman, A.R., Anderson, P.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Directed expression of the growth-associated protein B-50/GAP-43 to olfactory neurons in transgenic mice results in changes in axon morphology and extraglomerular fiber growth. Holtmaat, A.J., Dijkhuizen, P.A., Oestreicher, A.B., Romijn, H.J., Van der Lugt, N.M., Berns, A., Margolis, F.L., Gispen, W.H., Verhaagen, J. J. Neurosci. (1995) [Pubmed]
  15. Differential expression of MARCKS and other calmodulin-binding protein kinase C substrates in cultured neuroblastoma and glioma cells. Rosé, S.D., Cook, H.W., Palmer, F.B., Ridgway, N.D., Byers, D.M. J. Neurochem. (1994) [Pubmed]
  16. Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice. Thompson, S.N., Gibson, T.R., Thompson, B.M., Deng, Y., Hall, E.D. Exp. Neurol. (2006) [Pubmed]
  17. Prenatal differentiation of mouse vomeronasal neurones. Tarozzo, G., Cappello, P., De Andrea, M., Walters, E., Margolis, F.L., Oestreicher, B., Fasolo, A. Eur. J. Neurosci. (1998) [Pubmed]
  18. Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha. Wilcoxon, J.S., Nadolski, G.J., Samarut, J., Chassande, O., Redei, E.E. Behav. Brain Res. (2007) [Pubmed]
  19. Freeze-substitution and Lowicryl HM20 embedding of fixed rat brain: suitability for immunogold ultrastructural localization of neural antigens. van Lookeren Campagne, M., Oestreicher, A.B., van der Krift, T.P., Gispen, W.H., Verkleij, A.J. J. Histochem. Cytochem. (1991) [Pubmed]
  20. Age-related effects of ethanol consumption on triiodothyronine and retinoic acid nuclear receptors, neurogranin and neuromodulin expression levels in mouse brain. Boucheron, C., Alfos, S., Enderlin, V., Husson, M., Pallet, V., Jaffard, R., Higueret, P. Neurobiol. Aging (2006) [Pubmed]
  21. Abnormal thalamocortical pathfinding and terminal arbors lead to enlarged barrels in neonatal GAP-43 heterozygous mice. McIlvain, V.A., Robertson, D.R., Maimone, M.M., McCasland, J.S. J. Comp. Neurol. (2003) [Pubmed]
  22. Analysis of the role of calmodulin binding and sequestration in neuromodulin (GAP-43) function. Gamby, C., Waage, M.C., Allen, R.G., Baizer, L. J. Biol. Chem. (1996) [Pubmed]
  23. Transgenic expression of B-50/GAP-43 in mature olfactory neurons triggers downregulation of native B-50/GAP-43 expression in immature olfactory neurons. Holtmaat, A.J., Huizinga, C.T., Margolis, F.L., Gispen, W.H., Verhaagen, J. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  24. GAP-43 mediates retinal axon interaction with lateral diencephalon cells during optic tract formation. Zhang, F., Lu, C., Severin, C., Sretavan, D.W. Development (2000) [Pubmed]
  25. The basic helix-loop-helix differentiation factor Nex1/MATH-2 functions as a key activator of the GAP-43 gene. Uittenbogaard, M., Martinka, D.L., Chiaramello, A. J. Neurochem. (2003) [Pubmed]
  26. Quantitative analysis of expression of NeuroD, GAP43 and receptor tyrosine kinase B in developing mouse olfactory neuroepithelium. Yasui, R., Hasegawa, M., Doi, K., Shimizu, K., Ohtuski, N., Ishida, H., Nibu, K. Acta oto-laryngologica. Supplementum. (2004) [Pubmed]
  27. Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins. Quattrone, A., Pascale, A., Nogues, X., Zhao, W., Gusev, P., Pacini, A., Alkon, D.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  28. NFAT-3 is a transcriptional repressor of the growth-associated protein 43 during neuronal maturation. Nguyen, T., Lindner, R., Tedeschi, A., Forsberg, K., Green, A., Wuttke, A., Gaub, P., Di Giovanni, S. J. Biol. Chem. (2009) [Pubmed]
  29. Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin. Botchkarev, V.A., Eichmüller, S., Johansson, O., Paus, R. J. Comp. Neurol. (1997) [Pubmed]
  30. Comparison of interspecific to intersubspecific backcrosses demonstrates species and sex differences in recombination frequency on mouse chromosome 16. Reeves, R.H., Crowley, M.R., Moseley, W.S., Seldin, M.F. Mamm. Genome (1991) [Pubmed]
  31. Co-induction of growth-associated protein GAP-43 and neuronal nitric oxide synthase in the cochlear nucleus following cochleotomy. Chen, T.J., Huang, C.W., Wang, D.C., Chen, S.S. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2004) [Pubmed]
  32. Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. Koponen, E., Lakso, M., Castrén, E. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  33. Genetic mapping of two DNA markers, D16Ros1 and D16Ros2, flanking the mutation site in the chakragati mouse, a transgenic insertional mutant. Ratty, A.K., Matsuda, Y., Elliott, R.W., Chapman, V.M., Gross, K.W. Mamm. Genome (1992) [Pubmed]
  34. Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human. Kosik, K.S., Orecchio, L.D., Bruns, G.A., Benowitz, L.I., MacDonald, G.P., Cox, D.R., Neve, R.L. Neuron (1988) [Pubmed]
  35. Targeted overexpression of the neurite growth-associated protein B-50/GAP-43 in cerebellar Purkinje cells induces sprouting after axotomy but not axon regeneration into growth-permissive transplants. Buffo, A., Holtmaat, A.J., Savio, T., Verbeek, J.S., Oberdick, J., Oestreicher, A.B., Gispen, W.H., Verhaagen, J., Rossi, F., Strata, P. J. Neurosci. (1997) [Pubmed]
  36. In vivo post-transcriptional regulation of GAP-43 mRNA by overexpression of the RNA-binding protein HuD. Bolognani, F., Tanner, D.C., Merhege, M., Deschênes-Furry, J., Jasmin, B., Perrone-Bizzozero, N.I. J. Neurochem. (2006) [Pubmed]
  37. Excitatory synaptic transmission and its modulation by PKC is unchanged in the hippocampus of GAP-43-deficient mice. Capogna, M., Fankhauser, C., Gagliardini, V., Gähwiler, B.H., Thompson, S.M. Eur. J. Neurosci. (1999) [Pubmed]
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