Leukemia inhibitory factor inhibits neuronal development and disrupts synaptic organization in the mouse retina

Abstract

Leukemia inhibitory factor (LIF) belongs to the interleukin-6 cytokine family, all members of which signal through the common gp130 receptor. Neurotrophic members of this cytokine family are known to arrest photoreceptor maturation and are likely to regulate maturation of other retinal neurons as well. We have used transgenic mice that constitutively express LIF beginning in embryonic development to determine its effects on synaptic organization and molecular maturation of all classes of retinal neurons. LIF reduced the numbers of cells showing markers characteristic of mature cells of all neuronal classes and caused synaptic ectopia. The net effect was disrupted morphological development and disturbed synaptic organization. Our study suggests that cytokines signaling through gp130 are capable of regulating many aspects of neuronal differentiation in the retina, including synaptic targeting.

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

“…The disorganization in the normal retinal layering was associated with the loss of inner and outer segments, which has been also observed by others (Schlichtenbrede et al, 2003;Song et al, 2005), Similar alterations were found in the retinas of transgenic mice that constitutively express leukemia inhibitory factor Sherry et al, 2005). Although IS are beginning to bud in the 4 week-old canine peripheral retina, IS and OS are fully formed when the retina has reached maturity at 7-8 weeks of age.…”

Preconditioning-induced protection of photoreceptors requires activation of the signal-transducing receptor gp130 in photoreceptors

“…However, little is known regarding the mechanism of protection. In addition, several adverse consequences of overstimulation of this receptor have been reported, including gliosis (38), inhibition of neural function (17,19,39,40), and altered developmental states (41)(42)(43). Therefore, specific knowledge of the mechanism for gp130-induced protection is essential for the development of neuroprotective therapies to avoid these side effects.…”

Function and Mechanism of CNTF/LIF Signaling in Retinogenesis

“…CNTF/LIF has been shown to strongly inhibit differentiation of rod photoreceptors in both mouse and rat retinas (Ezzeddine et al 1997; Neophytou et al 1997; Kirsch et al 1998; Schulz-Key et al 2002; Sherry et al 2005; Elliott et al 2006). Both CNTFRα and LIFRβ knockout retinas display increased proportions of rod photoreceptors when cultured as explants for 10 days in-vitro starting from post-natal day 0 (Ezzeddine et al 1997).…”

“…This effect is interesting as rod and bipolar cells are derived from common postnatal progenitor cells that share key transcription factors including Otx2 and Crx (Furukawa et al 1997; Koike et al 2007). Nonetheless, transgenic mice that overexpress LIF during embryogenesis do not overproduce bipolar cells in-vivo (Sherry et al 2005), suggesting that timing and/or duration of signaling may play a role in the cellular effects.…”