Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity.
Individuals with the neurofibromatosis type 1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the CNS. In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/-) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/- CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK (MAP kinase kinase) or PI3-K (phosphatidylinositol 3-kinase) inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/- CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/- mice after optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.
Brown
Jacquelyn A
JA
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Gianino
Scott M
SM
Gutmann
David H
DH
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D006580:Genetic Carrier Screening; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009409:Nerve Crush; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology
D000242:Cyclic AMP
J Cell Biol. 1993 May;121(3):665-72
8486743
Curr Opin Cell Biol. 1990 Feb;2(1):80-5
2139335
Nature. 1992 Apr 23;356(6371):713-5
1570015
Curr Biol. 2005 Nov 8;15(21):1961-7
16271875
J Neuropathol Exp Neurol. 2009 May;68(5):542-51
19525901
Neurosci Lett. 1999 Jan 8;259(2):111-4
10025570
Mol Cell Biol. 1997 Feb;17(2):862-72
9001241
Cell. 2008 Oct 31;135(3):549-60
18984165
J Invest Dermatol. 1999 Jun;112(6):835-42
10383727
J Neurosci Res. 1994 Jun 15;38(3):248-58
7932862
Vis Neurosci. 2005 Sep-Oct;22(5):661-76
16332277
Ann Neurol. 1997 Feb;41(2):143-9
9029062
Neurology. 1997 Apr;48(4):1121-7
9109916
Cell. 1995 Sep 8;82(5):733-42
7671302
J Biol Chem. 2001 Mar 9;276(10):7240-5
11080503
Cancer Res. 2007 Sep 15;67(18):8588-95
17875698
Nat Neurosci. 2002 Feb;5(2):95-6
11788835
Neuron. 2004 Jun 10;42(5):717-30
15182713
Mol Cell Neurosci. 2003 Jan;22(1):49-61
12595238
Cell. 1992 Apr 17;69(2):265-73
1568246
Circulation. 2007 Nov 6;116(19):2148-56
17967772
Glia. 2007 Jan 1;55(1):1-12
16998865
Mol Biol Cell. 2009 Feb;20(4):1167-79
19109430
J Exp Med. 2000 Jan 3;191(1):181-8
10620616
Cell Stem Cell. 2007 Oct 11;1(4):443-57
18371380
Genes Dev. 2001 Apr 1;15(7):859-76
11297510
Neuron. 1990 Sep;5(3):373-81
2169272
J Neurosci. 2003 Aug 6;23(18):7207-17
12904481
J Neurosci. 2007 Feb 21;27(8):2124-34
17314307
Hum Mol Genet. 2007 May 1;16(9):1098-112
17400655
Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2442-9
12091449
J Dev Behav Pediatr. 1986 Jun;7(3):175-9
3088045
Hum Mol Genet. 2008 Oct 1;17(19):2956-66
18614544
J Neurosci Res. 2003 Dec 1;74(5):726-35
14635223
Mol Cell Neurosci. 2000 Apr;15(4):398-407
10845775
Exp Neurol. 2004 Apr;186(2):124-33
15026251
Am J Physiol. 1993 Aug;265(2 Pt 1):C422-31
8396326
J Biol Chem. 1999 Sep 3;274(36):25842-8
10464325
J Neurosci. 2003 Oct 1;23(26):8949-54
14523097
J Neurosci. 1998 Dec 15;18(24):10420-8
9852579
Development. 2005 Dec;132(24):5577-88
16314489
Am J Med Genet. 1999 Mar 26;89(1):45-52
10469436
Dev Neurobiol. 2009 Sep 1;69(10):633-46
19513995
Neurology. 2005 Oct 11;65(7):1037-44
16217056
Neuron. 1988 Nov;1(9):791-803
2908449
Dev Med Child Neurol. 1995 May;37(5):427-36
7768342
Cancer Res. 2003 Dec 15;63(24):8573-7
14695164
Nature. 2002 Jan 31;415(6871):526-30
11793011
J Biochem. 2009 Jun;145(6):771-81
19254925
Cancer Res. 2007 May 15;67(10):4790-9
17510408
FASEB J. 2006 Apr;20(6):785-7
16467371
Cancer Res. 2005 Jan 1;65(1):236-45
15665300
Blood. 2008 Dec 1;112(12):4646-54
18768391
Mol Cell Endocrinol. 1997 Jun 20;130(1-2):93-100
9220025
Nat Genet. 1996 Feb;12(2):144-8
8563751
J Assoc Res Otolaryngol. 2001 Dec;2(4):377-87
11833610
Neuro Oncol. 2007 Oct;9(4):430-7
17704361
Methods Mol Biol. 2007;356:427-34
16988421