Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth

DeChiara, Thomas M.; Vejsada, R.; Poueymirou, William; Acheson, Ann; Suri, Chitra; Conover, Joanne C.; Friedman, Beth; McClain, Joyce; Li, Pan; Stahl, Neil; Ip, Nancy Y.; Kato, Ann C.; Yancopouloš, George D.

doi:10.1016/0092-8674(95)90172-8

Cited by 350 publications

(268 citation statements)

References 66 publications

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“…In this regard, two members of the IL-6 family of cytokines, LIF and CNTF, have been shown to play an important role in maintaining the viability of motoneurons in long- term culture and also in the in vivo context (21)(22)(23)(24)(25). Interestingly, mice that harbor a targeted disruption of the ␣ subunit of the CNTF receptor or the ␤ receptor of the LIF receptor die shortly after birth and display a severe loss of more than 48% of the motoneurons in the spinal cord and brain stem (26,27). These results suggest that ligands that activate gp130 may play a critical physiological role in regulating survival of terminally differentiated cell types in vivo.…”

Section: Ct-1-dependent Pathways Promote Myocardial Cell Survival Viamentioning

confidence: 99%

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

Sheng¹,

Knowlton

Chen³

et al. 1997

Journal of Biological Chemistry

377

212

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Cardiac muscle cell survival plays a critical role in maintaining the normal function of the heart and possibly in cardiac development. Adult cardiac muscle cells are terminally differentiated and therefore have lost their proliferative capacity. In contrast to skeletal muscle, the myocardium does not contain satellite heart muscle cells, and irreversible heart injury results in scarring and an eventual decrease in global cardiac function. In response to mechanical stimuli and hemodynamic stress, the adult myocardium activates an adaptive hypertrophic response that is characterized by an increase in myocardial cell size without a concomitant increase in myocyte number (For review, see Refs. 1 and 2). However, during longstanding exposure to hypertension or other forms of hemodynamic stress, a distinct form of myocardial cell hypertrophy can be activated in which the heart becomes dilated and individual cardiac myocytes exhibit an increase in cell length, reflecting the addition of new sarcomeric units in series (3,4). This dilatation of the heart is usually accompanied by fibrosis, microscarring, and the loss of viable cardiac myocytes throughout the myocardium. As a result of cardiac dilatation and myocyte dropout, the myocardium ultimately develops an irreversible loss of function and ensuing cardiac muscle failure (4). As such, the identification of the signaling pathways that mediate distinct forms of cardiac muscle cell hypertrophy, dysfunction, and cardiac muscle cell survival are critical to the ultimate elucidation of the molecular basis of cardiac muscle failure.By coupling expression cloning with an embryonic stem cellbased model of in vitro cardiogenesis (5), recent studies have identified cardiotrophin 1 (CT-1), 1 a novel cardiac cytokine that was isolated in a search for new factors that induce cardiac myocyte hypertrophy (5). CT-1 is a new member of the IL-6 family of cytokines that exert their biological effects through the shared signaling subunit gp130 (3, 5-7) and can activate a distinct form of myocardial cell hypertrophy that is characteristic of volume overload cardiac hypertrophy at the molecular, morphological, and cellular levels (3). Importantly, cardiotrophin 1 has been shown to be capable of promoting survival of both embryonic and neonatal rat ventricular muscle cells (8). Recent studies have demonstrated that CT-1 exerts its effects on cardiac muscle cell hypertrophy through promoting the heterodimerization of gp130 with the leukemia inhibitory factor

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Section: Ct-1-dependent Pathways Promote Myocardial Cell Survival Viamentioning

confidence: 99%

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

Sheng¹,

Knowlton

Chen³

et al. 1997

Journal of Biological Chemistry

377

212

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“…These results contradict the prior analysis of CNTF−/− mice by Siegel et al (2000), which reported sprouting at only about 10% of terminals in LG muscles in response to any of the sprouting stimuli. One explanation for the discrepancy may be that the previous investigators studied a different line of CNTF−/− mice, which was not available to us (DeChiara et al, 1995). However, the CNTF null mice used in the present study (Masu et al, 1993) share the C57BL/6 background of the line used by Siegel et al, and display similar motor neuron deficits (Masu et al, 1993,DeChiara et al, 1995.…”

Section: Discussionmentioning

confidence: 73%

“…One explanation for the discrepancy may be that the previous investigators studied a different line of CNTF−/− mice, which was not available to us (DeChiara et al, 1995). However, the CNTF null mice used in the present study (Masu et al, 1993) share the C57BL/6 background of the line used by Siegel et al, and display similar motor neuron deficits (Masu et al, 1993,DeChiara et al, 1995. The discrepancy is also unlikely to be attributable to variable sprouting competence among muscles examined in the two studies (Brown et al, 1980,Prakash et al, 1999,Pun et al, 2002,De Winter et al, 2006,Burns et al, 2007, because LAL, EDL and LG muscles are all fast-twitch muscles.…”

Section: Discussionmentioning

confidence: 92%

Ciliary neurotrophic factor is not required for terminal sprouting and compensatory reinnervation of neuromuscular synapses: Re-evaluation of CNTF null mice

Wright

Son

2007

Experimental Neurology

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Loss of synaptic activity or innervation induces sprouting of intact motor nerve terminals that adds or restores nerve-muscle connectivity. Ciliary neurotrophic factor (CNTF) and terminal Schwann cells (tSCs) have been implicated as molecular and cellular mediators of the compensatory process. We wondered if the previously reported lack of terminal sprouting in CNTF null mice was due to abnormal reactivity of tSCs. To this end, we examined nerve terminal and tSC responses in CNTF null mice using experimental systems that elicited extensive sprouting in wildtype mice. Contrary to the previous report, we found that motor nerve terminals in the null mice sprout extensively in response to major sprouting-stimuli such as exogenously applied CNTF per se, botulinum toxinelicited paralysis, and partial denervation by L4 spinal root transection. In addition, the number, length and growth patterns of terminal sprouts, and the extent of reinnervation by terminal or nodal sprouts, were similar in wildtype and null mice. tSCs in the null mice were also reactive to the sprouting-stimuli, elaborating cellular processes that accompanied terminal sprouts or guided reinnervation of denervated muscle fibers. Lastly, CNTF was absent in quiescent tSCs in intact, wildtype muscles and little if any was detected in reactive tSCs in denervated muscles. Thus, CNTF is not required for induction of nerve terminal sprouting, for reactivation of tSCs, and for compensatory reinnervation after nerve injury. We interpret these results to support the notion that compensatory sprouting in adult muscles is induced primarily by contact-mediated mechanisms, rather than by diffusible factors.

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“…The gp130 cytokine family is characterized by functional redundancy, and the phenotypes of mice lacking individual cytokines [12,17,28,29,45] are much less severe than the phenotypes of mice lacking their shared receptors [10,30,46]. Nonetheless, the early and robust expression of CT-1 in the developing heart tube, and the sustained expression of CT-1 in the adult heart, suggested that CT-1 played a unique role in promoting cardiac myocyte survival and hypertrophy during development and after injury.…”

Section: Discussionmentioning

confidence: 99%

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

et al. 2006

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Cardiotrophin-1 (CT-1) was identified as a growth factor for cardiac myocytes, and CT-1 protects myocytes from cell death. Adult CT-1−/− mice exhibit neural deficits including the loss of preganglionic sympathetic neurons, but their autonomic and cardiac parameters have not been examined. We used these mice to determine if the absence of CT-1 or loss of preganglionic sympathetic input altered heart rate, left ventricular pressure, cardiac contractility (dP/dt), or cell death following ischemia-reperfusion. Basal heart rate was increased in CT-1−/− mice, and this difference was abolished by ganglionic block. Left ventricular pressure and dP/dt were unchanged. Dobutamine stimulated similar increases in heart rate and dP/dt in both genotypes, but ventricular pressure was significantly lower in CT-1 nulls. Cardiac expression of interleukin-6 (IL-6) mRNA was increased significantly in CT-1 null mice, while leukemia inhibitory factor (LIF) mRNA was unchanged. Infarct size normalized to area at risk was no different in CT-1 −/− mice (33.8±1.0 % vs. 37.7±3.2 % WT) 24 hours after ischemia-reperfusion. Induction of IL-6 mRNA after infarct was significantly abrogated in CT-1 null mice compared to wild type mice, but LIF mRNA induction remained significant in CT-1 null mice and might contribute to cardiac protection in the absence of CT-1.

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Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth

Cited by 350 publications

References 66 publications

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

Ciliary neurotrophic factor is not required for terminal sprouting and compensatory reinnervation of neuromuscular synapses: Re-evaluation of CNTF null mice

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

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