Astrocyte-derived transgene GDNF promotes complete and long-term survival of adult facial motoneurons following avulsion and differentially regulates the expression of transcription factors of AP-1 and ATF/CREB families.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs). We have previously demonstrated that overexpression of GDNF in astrocytes of GFAP-GDNF mice promotes long-term survival of neonatal MNs after facial nerve axotomy. In the present study, we investigated whether astrocyte-derived GDNF could also have a neuroprotective effect on adult MNs following facial nerve avulsion. We also examined avulsion- and GDNF-induced changes in the expression pattern of several members of the AP-1 and ATF/CREB families of transcription factors, which are involved in the fate determination of neurons following injury. We demonstrated that GDNF promotes complete rescue of avulsed MNs for at least 4 months post-injury. Transgene GDNF significantly upregulates c-Jun expression in naive MNs, further upregulates injury-induced c-Jun expression in facial MNs, and results in its activation in most surviving MNs. No significant changes were found in c-Fos expression. We found that GDNF has an opposing effect on ATF2 and ATF3 expression. It dramatically downregulates increased levels of ATF3 in response to injury, whereas the expression of ATF2, which is normally reduced after injury, is completely preserved in GFAP-GDNF mice. Our data suggest that maintenance of high levels of ATF2 in injured MNs could be crucial in modulating c-Jun function, and c-Jun/ATF2 signaling could be involved in GDNF-mediated survival of mature MNs.
Parsadanian
Alexander
A
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA. parsadaniana@neuro.wustl.edu
Pan
Yanchun
Y
Li
Wen
W
Myckatyn
Terence M
TM
Brakefield
Danielle
D
D051696:Activating Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D020220:Facial Nerve Injuries / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D005810:Multigene Family; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes / Q000502:physiology
D051696:Activating Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1