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

• Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice [1].
• Here we show that co-expressing two major growth cone proteins, GAP-43 and CAP-23, can elicit long axon extension by adult dorsal root ganglion (DRG) neurons in vitro [2].
• Studies on the relationship of the B700 and B50 murine melanoma antigens [3].
• Perforant path long-term potentiation (LTP) in intact mouse hippocampal dentate gyrus increased the neuron-specific, growth-associated protein GAP-43 mRNA in hilar cells 3 days after tetanus, but surprisingly not in granule cells, the perforant path target [4].
• After subcloning into a plasmid vector containing the bacterial Eco-gpt gene as a selectable marker, the Thy-1 gene was introduced into the Thy-1-deficient mouse lymphoma AKR1 (Thy-1-d), and the rat neuronal cell line, B50 [5].

Psychiatry related information on Gap43

• Importantly, no significant impairments in cued conditioning or on tests of nociceptive or auditory perception were observed in the heterozygous knockout, indicating that the observed impairments were unlikely related to performance or acquisition factors and are the result of reduced GAP-43 levels in the hippocampus [6].
• Therefore, an increase in both PKC gamma and neuromodulin contributed to the increased phosphorylation of neuromodulin during electroshock seizure [7].
• Since GAP-43 is involved in some forms of neural plasticity, we also compared the duration of the critical period for lesion-induced plasticity in both genotypes [8].

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

• Here we show that neuroectodermal differentiation stimulated by retinoic acid (RA) in the embryonal carcinoma (EC) line P19 is accompanied by upregulation of GAP-43 expression in neuroepithelial precursor cells [11].

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

• Some other markers of nasal chemosensory neurones, such as GAP-43/B-50, Protein Gene Product 9.5 (PGP 9.5) and carnosine are also transiently expressed in this ectopic site [17].
• Thyroid hormone-regulated genes potentially responsible for the learning deficit found in TRalpha(o/o) mice include GR, RC3 and GAP-43 [18].
• Freeze-substitution of tissue was performed with anhydrous methanol and 0.5% uranyl acetate at -90 degrees C. Semi-thin Lowicryl sections were used for light microscopic visualization of B-50 in the ventromedial mesencephalic central gray substance [19].
• Age-related effects of ethanol consumption on triiodothyronine and retinoic acid nuclear receptors, neurogranin and neuromodulin expression levels in mouse brain [20].
• Using serotonin transporter (5HT-T) histochemistry to label thalamocortical afferents (TCAs), we found no obvious abnormalities in other somatosensory areas or primary visual cortex of GAP-43 (+/-) mice [21].

Physical interactions of Gap43

• Here we analyze the role of calmodulin binding by neuromodulin in these responses [22].

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].

References