Ординатура / Офтальмология / Английские материалы / Retinal Development_Sernagor, Eglen, Harris, Wong_2006

Figure 8.5 Migration of OPCs from the region of the optic chiasm into the optic nerve in mouse embryos. The OPCs were visualized as LacZ-positive cells from a transgenic mouse line in which LacZ expression is under the control of regulatory sequences of the myelin protein plp. (A) E14.5 (B) E 15.5 (C) E16.5 (D) E17.5. Gestation in mouse is 20 days. The inset in C shows the long cytoplasmic extensions of the LacZ-positive cell profiles parallel to the chiasm–retinal axis. poa, pre-optic area; ch, optic chiasm; r, retina. Scale A, B = 110 µm; C, D = 85 µm; C inset = 25 µm. (Modified from Spassky et al., 2002.)

use for pathfinding in the optic nerve and in the ventral diencephalon region (Sugimoto et al., 2001; Spassky et al., 2002). In the case of the OPCs, however, these signals result in cell migration away from the brain towards the retina, whereas RGC axons travel in the opposite direction towards their CNS targets.

Evidence suggests that OPC migration into the optic nerve involves at least two classes of guidance molecules, the Netrins and Semaphorins. Oligodendrocyte precursor cells express Neuropilin 1 and 2, transmembrane proteins involved in mediating cell responsiveness to various Semaphorins (Raper, 2000; Bagri and Tessier-Lavigne, 2002). In addition, OPCs also express DCC and Unc5H1, proteins that serve as Netrin receptors (Keino-Masu et al., 1996; Hong et al., 1999). In vitro, OPCs exposed to sources and gradients of Netrin or Sema3, show a repellant behaviour and move away from these guidance molecules (Sugimoto et al., 2001; Spassky et al., 2002). It is proposed that a source of these guidance molecules

is present at the ventral midline regions of the diencephalon and that a gradient of these guidance molecules exists maximally at the brain and drops off in the direction towards the retina. Such a graded distribution of a chemorepellant is thought to force OPCs to migrate away from the ventral diencephalon into the optic nerve towards the retina. Of note, similar repellant mechanisms for glial migration involving Netrin have been proposed in other regions of the CNS (Tsai et al., 2003).

The idea that OPC migration into the optic nerve shares a common molecular basis as RGC axon pathfinding is attractive in that it conserves highly successful mechanisms through which cells sense and respond to their environment and thus limit the number of different molecular system that must be used. However, in vivo evidence for a shared molecular basis with axon pathfinding is more difficult to obtain. Standard targeted disruption of genes encoding guidance molecules or their receptors will likely affect RGC axon guidance. Since RGC axons themselves may act as a source of additional guidance molecules for OPC migration or provide a physical substrate for cell migration, abnormalities of OPC movement in such experiments will require careful interpretation. The use of techniques that allow specific spatiotemporal alteration of gene function in OPCs may be one revealing approach.

8.22Stop signals at the optic nerve head

A well-known feature of the optic nerve myelination is that RGC axons are not myelinated until some distance proximal, away from the optic nerve head and RGC axons are not myelinated in the retina. (Rabbits are an exception to this rule.) This absence of axon myelination in the retina is thought to be critical for maintaining optical clarity necessary for light transduction. The region of the optic nerve lacking myelination corresponds to the area of the lamina cribosa, a region immediately adjacent to the optic nerve head with a specialized cellular and structural composition (Ffrench-Constant et al., 1988; Perry and Lund, 1990; Ye and Hernandez, 1995). The role of the lamina cribosa in the adult optic nerve is unknown but may involve the provision of mechanical support for this unmyelinated region of the optic nerve. Its importance is highlighted by the fact that alterations in the cellular and molecular composition of the lamina cribosa region is found in glaucoma (Hernandez, 2000), and is thought to contribute to the retrograde RGC cell death characteristic of this disease.

It is possible that structural and molecular elements in the developing lamina cribosa serve a role restricting OPC migration and invasion of the retina (Ffrench-Constant et al., 1988). The nature of such signals is unknown at present. One possible candidate is Netrin, which is highly expressed at the optic nerve head and is responsible for RGC axon exit from the retina into the optic nerve (Deiner et al., 1997). As discussed above, Netrin has also been found to inhibit OPC migration (Sugimoto et al., 2001) and may thus be in a correct location to prevent OPC movement into the retina. In the developing spinal cord, CXCL1 and 2, members of the chemokine family has been shown to act as a stop signal for OPC migration (Tsai et al., 2002).

8.23Concluding remarks

Optic nerve development represents a microcosm of many of the important events occurring throughout the developing nervous system such as axon extension, glial development, axon– glial interactions and myelination. The specific absence of neurons in the optic nerve provides an added degree of convenience in experimental design and interpretation. Although the topic of this chapter is optic nerve development, one should also not lose sight of the fact that the adult optic nerve is a crucial CNS axon tract whose normal function is essential for vision and, thus, for much of behaviour. Major eye diseases such as glaucoma and various other traumatic insults that compromise optic nerve function represent significant causes of visual impairment. For example, glaucoma is a leading cause of blindness affecting an estimated 70 million individuals worldwide (Quigley, 1996; Fraser and Wormald, 2004). Although the precise disease mechanism is yet to be completely defined, it is widely recognized as an optic neuropathy in which cellular and molecular changes within the optic nerve cause the retrograde apoptotic cell death of retinal ganglion cells (Hernandez, 2000; Fraser and Wormald, 2004). While progress against this disease will surely require efforts on multiple fronts, a better understanding of the mechanisms that work together to construct an optic nerve during embryonic development may inform on aspects of basic biology that can be manipulated as potential therapeutic strategies.

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blood vessels in the developing retina (Provis et al., 2000), although their role in the adult retina is less certain. M¨uller cell processes also contact the vessels at the vitreal surface, as well as the capillaries that descend into the inner nuclear layer (Holl¨ander et al., 1991; Distler and Dreher, 1996), and it is not clear how the functions of M¨uller cells and astrocytes differ. Understanding the role of glia in the development of blood vessels may also provide insights into the mechanisms underlying the abnormal growth of blood vessels in several diseases of the retina, including retinopathy of prematurity and diabetic retinopathy.

In the adult retina, glial cells can best be understood in terms of their morphological and functional relationships with neurons and the vasculature. In this chapter, we have largely taken this approach in reviewing the literature on retinal glial cell development.

9.2Retinal histogenesis

The formation of the retina proceeds through several steps, including the differentiation of progenitors into glia and several classes of neurons, cell migration and formation of the retinal layers and synaptogenesis. M¨uller glial cells may influence each of these steps in retinal development.

9.2.1 Origin of retinal glia

M¨uller cells are generated from progenitor cells within the retina (Turner, 1987), while astrocytes immigrate into the retina from the optic nerve (Watanabe and Raff, 1988). M¨uller cells leave the cell cycle relatively late in retinal development (Dyer and Cepko, 2000; Vetter and Moore, 2001; Rapaport et al., 2004), after the generation of most classes of retinal neurons. There is no consensus regarding the definition of a ‘mature’ M¨uller cell. M¨uller cells are capable of re-entering the cell cycle during ‘reactive gliosis’ in response to retinal injury or disease (Dyer and Cepko, 2000; Bringmann and Reichenbach, 2001). M¨uller cells may even serve as neurogenic progenitor cells in the adult retina (Reh and Fischer, 2001; Fischer and Reh, 2003), a topic addressed in Chapter 15.

9.2.2Radial glia and retinal histogenesis

In other regions of the central nervous system, radial glia serve as a scaffold for neuronal migration (Hatten, 1990). There is no direct evidence that M¨uller cells serve this function in the retina, although parallels have been drawn with events in cortex and cerebellum. (For the purpose of this discussion, the term ‘M¨uller cell’ will refer to a radial glial cell of indeterminate maturity.) Clonal analyses and observations of static relationships between columns of neurons and single M¨uller cells have led to speculation that M¨uller cells are a scaffold for migration of later-generated neurons (Brittis and Silver, 1995; Reichenbach and Robinson, 1995; Sharma and Johnson, 2000).