Multiple neurotrophic signalling: certain TGF molecules are involved in retinal development and maturation, but do they complement one another's actions?

The whole is more than a sum of its parts Holland, 1998 Survival and apoptosis of retinal neurones are critical processes occurring during development and maturation. In keeping with the general concept of trophic stimulation, we have found that a group of active molecules can regulate the phenotypic expression of retinal neural cells, allowing them to survive and become mature neurones, whereas, in their absence, many of the cells would have died. These trophic molecules have a definite role in activating signal transduction pathways during certain events in eye development and maturation. Do these molecules from different families that act directly on cell survival and indirectly on apoptosis, operate at different times, or do they act together co-ordinately and synchronously, complementing one another’s actions? As Watkins wrote (Watkins, 2003): “transplantation for reviving retinas” also has aspects that could clearly be trophic. The answer to this key question is attracting much attention in modern neuroscience and provides a clear remit for the work of several research groups in cell biology. Trophic factors are essential during retinal development, triggering signalling cascades for survival, differentiation and maturation. They seem to play a key role in retinal regeneration. These trophic factors initially induce retinal cells to stay alive. In the same way, a considerable number of regular processes require minimum levels of trophic agents to act on specific target cell populations that express receptors for them. Many trophic molecules will consequently affect migration and extension of neurites to form a network of neuronal connections. Retinal cells die when they fail to receive greater exposure than the minimal trophic threshold, and in some instances this can be reversed by the action of other neuroprotective trophic processes. A family of neurotrophins (NGF, BDNF, NT-3, NT-4, NT-5) and their receptors (the Trks and p75) have clearly been identified as essential molecules in the regulation of eye development. Neurotrophins and their receptors have been shown to be present and active in the retina of several species, such as Xenopus (Cohen-Cory et al., 1996; Hutson and Bothwell, 2001; Lom and Cohen-Cory, 1999; Lom et al., 2002); chick (Allington et al., 2001; Butowt and von Bartheld, 2001; Cellerino and Kohler, 1997; Das et al., 2000; Frade, 2000; Gonzalez-Hoyuela et al., 2001; Hallbook et al., 1996; Herzog and von Bartheld, 1998; von Bartheld and Butowt, 2000; Wang et al., 2002); rat (Atkinson et al., 1999; Bosco and Linden, 1999; Caleo et al., 2000; Cheng et al., 2002; Cusato et al., 2002; Ding et al., 2001; Hirsch et al., 2000; Kashiwagi et al., 2000; Klocker et al., 2000; Rickman, 1999) and human (Cui et al., 1998; Nag and Wadhwa, 1999; Oku et al., 2002; Takano et al., 2002). Currently, several members of the transforming growth factor family (TGF) seem to be seriously involved in the same actions as neurotrophins on retinal cells. The corresponding receptors are expressed during developmental patterns, and work simultaneously with neurotrophins. Several colleagues have observed and started to focus on the novel action of these TGF trophic factors, which appear early during embryogenesis and start acting from the initiation of the developmental process of the eye, and act specifically on the regulation of retinal neurogenesis. * Corresponding author. Tel.: +54-221-4210112; fax: +54-221-4253320 E-mail address: [email protected] (N.G. Carri). Cell Biology International 27 (2003) 1033–1036 Cell Biology International