Elsevier

Experimental Neurology

Volume 172, Issue 1, November 2001, Pages 81-91
Experimental Neurology

Regular Article
Neurotrophin Receptor TrkB Activation Is Not Required for the Postnatal Survival of Retinal Ganglion Cells in Vivo

https://doi.org/10.1006/exnr.2001.7795Get rights and content

Abstract

During early postnatal development, apoptosis of retinal ganglion cells (RGCs) is regulated by target contact with the optic tectum. The neurotrophins BDNF and NT-4, but not NGF, prevent the apoptosis of retinal ganglion cells that is otherwise observed after target ablation or axotomy. Thus receptors activated by BDNF and NT-4 are candidates to mediate the early postnatal survival of RGCs. BDNF and NT-4, but not NGF, bind to all isoforms of the receptor TrkB, whether or not they contain a tyrosine kinase domain. To examine the roles of TrkB receptor isoforms in early postnatal survival, we compared RGC numbers in wild-type mice to those in a mutant lacking all isoforms of TrkB. Surprisingly, no reduction in RGCs was observed in the mutant at postnatal day 16, the latest age at which these animals are consistently viable, so TrkB signaling is not essential for target-dependent survival of these cells. In wild-type mice, RGCs also are lost gradually during adulthood, possibly due to oxidative stress. To determine whether TrkB signaling regulates this phase of RGC degeneration, RGC numbers were examined in a viable mutant of TrkB that expresses only about 25% the normal level of TrkB receptor kinase. Compared to controls, approximately 20% of the RGC were lost in mutant 3-month-old-animals. Thus, TrkB signaling is not required for survival of RGCs during the period of target-dependent survival, but does appear to reduce degeneration of RGCs in adult animals.

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    • The molecular basis of retinal ganglion cell death in glaucoma

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      Both exogenous BDNF administration and strategies that result in TrkB activation lead to enhanced RGC survival in acute and chronic models of optic nerve damage (Chen and Weber, 2001; Cheng et al., 2002; Di Polo et al., 1998; Hu et al., 2010b; Klöcker et al., 2000; Leaver et al., 2006; Mansour-Robaey et al., 1994; Mey and Thanos, 1993; Parrilla-Reverter et al., 2009; Peinado-Ramon et al., 1996). Paradoxically, the number of RGCs in BDNF or TrkB knockout mice have been shown to be similar to those found in wild-type animals (Cellerino et al., 1997; Pollock et al., 2003; Rohrer et al., 2001), suggesting that other neurotrophic factors compensate for the lack of BDNF or that BDNF signaling through TrkB is not required for RGC survival during development. Of interest, however, RGCs from BDNF null mice displayed hypomyelinated axons (Cellerino et al., 1997) which correlated with marked functional deficits (Rothe et al., 1999), a phenotype that might increase the vulnerability of these neurons to die following glaucomatous optic nerve damage.

    • Olfactory ensheathing glia: Repairing injury to the mammalian visual system

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      Similar to the rest of the CNS, it has been suggested that appropriate therapeutic manipulation of neurotrophic signaling pathways will promote the survival of injured RGCs (for reviews see Chierzi and Fawcett, 2001; Zhi et al., 2005; Harvey et al., 2006; Johnson et al., 2009). Among the neurotrophic factors known to promote survival of RGCs include BDNF (Rohrer et al., 2001; Leaver et al., 2006b; Peinado-Ramón et al., 1996), neurotrophin 4/5 (Cui et al., 2003; Peinado-Ramón et al., 1996), glial cell-derived neurotrophic factor (GDNF; Jiang et al., 2007) and ciliary neurotrophic factor (CNTF; Cui et al., 2003; Ji et al., 2004; Parrilla-Reverter et al., 2009). Numerous laboratories have tried to improve the efficacy of neurotrophic treatments to the injured optic nerve with varying success (Mey and Thanos, 1993; Chierzi and Fawcett, 2001; Harvey et al., 2006; Berry et al., 2008).

    • Neurotrophin roles in retinal ganglion cell survival: Lessons from rat glaucoma models

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      NT have important survival properties for adult neurons as well. The application of exogenous NT, especially BDNF, to isolated RGC prolongs their survival in culture (Johnson et al., 1986; Rodriguez-Tebar et al., 1989; Cohen-Cory and Fraser, 1994; Meyer-Franke et al., 1995; Rohrer et al., 2001). Importantly, multiple studies indicate that the intravitreal injection of BDNF prolongs injured, adult RGC survival in vivo (Mey and Thanos, 1993; Mansour-Robaey et al., 1994; Peinado-Ramon et al., 1996; Di Polo et al., 1998; Chen and Weber, 2001).

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    To whom correspondence should be addressed at the Storm Eye Institute, Room 707, Medical University of South Carolina, 167 Ashley Avenue, Charleston, SC 29425. Fax: (843) 792-1723. E-mail: [email protected].

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