Leukemia inhibitory factor promotes olfactory sensory neuronal survival via phosphoinositide 3-kinase pathway activation and Bcl-2.
Leukemia inhibitory factor (LIF), a neuropoietic cytokine, has been implicated in the control of neuronal development. We previously reported that LIF plays a critical role in regulating the terminal differentiation of olfactory sensory neurons (OSNs). Here, we demonstrate that LIF plays a complementary role in supporting the survival of immature OSNs. Mature OSNs express LIF, which may be elaborated in a paracrine manner to influence adjacent neurons. LIF null mice display more apoptotic immature neurons than do their wild-type littermates. LIF treatment of dissociated OSNs in vitro significantly reduces the apoptosis of immature OSNs. Double immunocytochemical analysis indicates that the survival of immature OSNs is dependent on the presence of LIF. LIF activates the phosphoinositide 3-kinase (PI3K) pathways and induces the expression of the antiapoptotic molecule Bcl-2 in OSNs, whereas inhibition of the PI3K pathway blocks LIF-dependent OSN survival and Bcl-2 induction. Thus, LIF plays a central role in maintaining the size and integrity of the population of immature neurons within the olfactory epithelium; this population is critical to the rapid recovery of olfactory function after injury. LIF may play a similar role elsewhere in the CNS and thus be important for manipulation of stem cell populations for therapeutic interventions.
Moon
Cheil
C
Department of Oral Anatomy and Neurobiology, Kyungpook National University School of Dentistry, Daegu, Republic of Korea.
Liu
Bridget Q
BQ
Kim
So Yeun
SY
Kim
Esther J
EJ
Park
Yun Ju
YJ
Yoo
Joo-Yeon
JY
Han
Hyung Soo
HS
Bae
Yong Chul
YC
Ronnett
Gabriele V
GV
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009831:Olfactory Mucosa / Q000166:cytology; D018034:Olfactory Receptor Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
D002867:Chromones; D004791:Enzyme Inhibitors; D053605:Leukemia Inhibitory Factor; D009025:Morpholines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases