The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway
Nerve growth factor (NGF) and insulin‐like growth factor‐1 (IGF‐1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neuri...
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description | Nerve growth factor (NGF) and insulin‐like growth factor‐1 (IGF‐1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF‐1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3‐K‐Akt‐GSK‐3 and Ras‐Raf‐MAPK) were performed using phospho‐specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3‐K pathway involving both Akt and GSK‐3 appeared to be more important for neurite extension and branching than MAPK‐dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho‐Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3‐K‐Akt‐GSK‐3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth. |
doi_str_mv | 10.1046/j.1471-4159.2003.01925.x |
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Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF‐1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3‐K‐Akt‐GSK‐3 and Ras‐Raf‐MAPK) were performed using phospho‐specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3‐K pathway involving both Akt and GSK‐3 appeared to be more important for neurite extension and branching than MAPK‐dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho‐Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3‐K‐Akt‐GSK‐3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.2003.01925.x</identifier><identifier>PMID: 12911620</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>adult sensory neurons ; Animals ; Biochemistry and metabolism ; Biological and medical sciences ; Blotting, Western ; Central nervous system ; Drug Synergism ; Enzyme Inhibitors - pharmacology ; Fundamental and applied biological sciences. Psychology ; Ganglia, Spinal - cytology ; glycogen synthase kinase ; Glycogen Synthase Kinase 3 - antagonists & inhibitors ; Glycogen Synthase Kinase 3 - metabolism ; Insulin-Like Growth Factor I - pharmacology ; insulin‐like growth factor‐1 ; mitogen activated protein kinase ; Mitogen-Activated Protein Kinases - metabolism ; nerve growth factor ; Nerve Growth Factor - pharmacology ; Neurites - drug effects ; Neurites - physiology ; Neurons, Afferent - cytology ; Neurons, Afferent - drug effects ; Neurons, Afferent - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; phosphoinositide 3‐kinase ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Sprague-Dawley ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 2003-09, Vol.86 (5), p.1116-1128</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4925-5e6108107e2402d4e99be1ecea4197fb0651e956a898644fa0fb25fe66da3c6a3</citedby><cites>FETCH-LOGICAL-c4925-5e6108107e2402d4e99be1ecea4197fb0651e956a898644fa0fb25fe66da3c6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1471-4159.2003.01925.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1471-4159.2003.01925.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15078729$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12911620$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jones, David M.</creatorcontrib><creatorcontrib>Tucker, Budd A.</creatorcontrib><creatorcontrib>Rahimtula, Masuma</creatorcontrib><creatorcontrib>Mearow, Karen M.</creatorcontrib><title>The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Nerve growth factor (NGF) and insulin‐like growth factor‐1 (IGF‐1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF‐1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3‐K‐Akt‐GSK‐3 and Ras‐Raf‐MAPK) were performed using phospho‐specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3‐K pathway involving both Akt and GSK‐3 appeared to be more important for neurite extension and branching than MAPK‐dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho‐Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3‐K‐Akt‐GSK‐3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth.</description><subject>adult sensory neurons</subject><subject>Animals</subject><subject>Biochemistry and metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Central nervous system</subject><subject>Drug Synergism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Ganglia, Spinal - cytology</subject><subject>glycogen synthase kinase</subject><subject>Glycogen Synthase Kinase 3 - antagonists & inhibitors</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Insulin-Like Growth Factor I - pharmacology</subject><subject>insulin‐like growth factor‐1</subject><subject>mitogen activated protein kinase</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>nerve growth factor</subject><subject>Nerve Growth Factor - pharmacology</subject><subject>Neurites - drug effects</subject><subject>Neurites - physiology</subject><subject>Neurons, Afferent - cytology</subject><subject>Neurons, Afferent - drug effects</subject><subject>Neurons, Afferent - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>phosphoinositide 3‐kinase</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcGO0zAURS0EYsrALyBvYJfg5zhOgsQCVbQUjQYWw9pynefWJXWKndDJju3s5hv5EpJpxWxZ2dI79177PkIosBSYkO92KYgCEgF5lXLGspRBxfP09gmZ_Rs8JTPGOE8yJvgFeRHjjjGQQsJzcgG8ApCczcjdzRZpHDyGjYudMxStRdNF2lp6vVxQ7Wu6Wi7-_L4H2nrqsQ-uQ7oJ7bHbUueprvumoxF9bMPwMG99fE9N63-NnugNTrpuTPm2otno88N5HcdMt_G6cX5DD7rbHvXwkjyzuon46nxeku-LTzfzz8nV1-Vq_vEqMWL8Y5KjBFYCK5ALxmuBVbVGQINaQFXYNZM5YJVLXValFMJqZtc8tyhlrTMjdXZJ3p58D6H92WPs1N5Fg02jPbZ9VFBBkeeiGMHyBJrQxhjQqkNwex0GBUxNa1A7NbWtprbVtAb1sAZ1O0pfnzP69R7rR-G59xF4cwZ0NLqxQXvj4iOXs6IseDVyH07c0TU4_PcD1Jfr-XTL_gJhK6WO</recordid><startdate>200309</startdate><enddate>200309</enddate><creator>Jones, David M.</creator><creator>Tucker, Budd A.</creator><creator>Rahimtula, Masuma</creator><creator>Mearow, Karen M.</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>200309</creationdate><title>The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway</title><author>Jones, David M. ; Tucker, Budd A. ; Rahimtula, Masuma ; Mearow, Karen M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4925-5e6108107e2402d4e99be1ecea4197fb0651e956a898644fa0fb25fe66da3c6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>adult sensory neurons</topic><topic>Animals</topic><topic>Biochemistry and metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Central nervous system</topic><topic>Drug Synergism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Ganglia, Spinal - cytology</topic><topic>glycogen synthase kinase</topic><topic>Glycogen Synthase Kinase 3 - antagonists & inhibitors</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Insulin-Like Growth Factor I - pharmacology</topic><topic>insulin‐like growth factor‐1</topic><topic>mitogen activated protein kinase</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>nerve growth factor</topic><topic>Nerve Growth Factor - pharmacology</topic><topic>Neurites - drug effects</topic><topic>Neurites - physiology</topic><topic>Neurons, Afferent - cytology</topic><topic>Neurons, Afferent - drug effects</topic><topic>Neurons, Afferent - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>phosphoinositide 3‐kinase</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jones, David M.</creatorcontrib><creatorcontrib>Tucker, Budd A.</creatorcontrib><creatorcontrib>Rahimtula, Masuma</creatorcontrib><creatorcontrib>Mearow, Karen M.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jones, David M.</au><au>Tucker, Budd A.</au><au>Rahimtula, Masuma</au><au>Mearow, Karen M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2003-09</date><risdate>2003</risdate><volume>86</volume><issue>5</issue><spage>1116</spage><epage>1128</epage><pages>1116-1128</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>Nerve growth factor (NGF) and insulin‐like growth factor‐1 (IGF‐1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF‐1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3‐K‐Akt‐GSK‐3 and Ras‐Raf‐MAPK) were performed using phospho‐specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3‐K pathway involving both Akt and GSK‐3 appeared to be more important for neurite extension and branching than MAPK‐dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho‐Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3‐K‐Akt‐GSK‐3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>12911620</pmid><doi>10.1046/j.1471-4159.2003.01925.x</doi><tpages>13</tpages></addata></record> |
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subjects | adult sensory neurons Animals Biochemistry and metabolism Biological and medical sciences Blotting, Western Central nervous system Drug Synergism Enzyme Inhibitors - pharmacology Fundamental and applied biological sciences. Psychology Ganglia, Spinal - cytology glycogen synthase kinase Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - metabolism Insulin-Like Growth Factor I - pharmacology insulin‐like growth factor‐1 mitogen activated protein kinase Mitogen-Activated Protein Kinases - metabolism nerve growth factor Nerve Growth Factor - pharmacology Neurites - drug effects Neurites - physiology Neurons, Afferent - cytology Neurons, Afferent - drug effects Neurons, Afferent - metabolism Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism phosphoinositide 3‐kinase Protein-Serine-Threonine Kinases Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Signal Transduction - drug effects Signal Transduction - physiology Vertebrates: nervous system and sense organs |
title | The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway |
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