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Role of FGF and MITF in Eye Development 3583 Development 127, 3581-3591 (2000) 3581 Printed in Great Britain © The Company of Biologists Limited 2000 DEV4340 Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF Minh-Thanh T. Nguyen and Heinz Arnheiter* Laboratory of Developmental Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA *Author for correspondence (e-mail: [email protected]) Accepted 27 May; published on WWW 20 July 2000 SUMMARY During vertebrate eye development, the optic vesicle is Conversely, the removal of the surface ectoderm results in partitioned into a domain at its distal tip that will give rise the maintenance of MITF in the distal optic epithelium, to the neuroretina, and another at its proximal base that lack of expression of the neuroretinal-specific CHX10 will give rise to the pigmented epithelium. Both domains transcription factor, and conversion of this epithelium are initially bipotential, each capable of giving rise to either into a pigmented monolayer. This phenomenon can be neuroretina or pigmented epithelium. The partitioning prevented by the application of fibroblast growth factor depends on extrinsic signals, notably fibroblast growth alone. In Mitf mutant embryos, parts of the future factors, which emanate from the overlying surface pigment epithelium become thickened, lose expression of ectoderm and induce the adjacent neuroepithelium to a number of pigment epithelium transcription factors, assume the neuroretinal fate. Using explant cultures of gain expression of neuroretinal transcription factors, and mouse optic vesicles, we demonstrate that bipotentiality eventually transdifferentiate into a laminated second of the optic neuroepithelium is associated with the retina. The results support the view that the bipotential initial coexpression of the basic-helix-loop-helix-zipper optic neuroepithelium is characterized by overlapping gene transcription factor MITF, which is later needed solely expression patterns and that selective gene repression, in the pigmented epithelium, and a set of distinct brought about by local extrinsic signals, leads to the transcription factors that become restricted to the separation into discrete expression domains and, hence, to neuroretina. Implantation of fibroblast growth factor- domain specification. coated beads close to the base of the optic vesicle leads to a rapid downregulation of MITF and the development of Key words: Retinal pigment epithelium, Neuroretina, an epithelium that, by morphology, gene expression, and Neuroepithelium, Optic vesicle culture, Transcription factor, lack of pigmentation, resembles the future neuroretina. Transcriptional repression, Mouse, Cell-fate specification INTRODUCTION Here we focus on the factors that specify the neuroretina (NR) and the retinal pigment epithelium (RPE). These two The development of the vertebrate eye, much as that of many tissues, though distinct in form and function, have a common other organs, is the result of complex, reciprocal interactions precursor, the cells of the anterior neuroepithelium that become between tissues of distinct embryological origin. The lens, for specified in an eye field. Normally, the epithelium forms an NR instance, is derived from the surface ectoderm that overlies the in the distal (inner) layer of the eye cup and an RPE in the optic vesicle, but without the juxtaposition of a normal optic proximal (outer) layer. However, there is a species-specific vesicle lens development is perturbed (Spemann, 1901; Lewis, period during which the fates of these two tissues remain 1904; Li et al., 1994; Porter et al., 1997; Furuta and Hogan, reversible. For instance, when in amphibians the eye is 1998; Kamachi et al., 1998). Conversely, without a proper lens experimentally inverted so that the outer layer comes to lie placode the optic vesicle remains rudimentary, and an optic cup adjacent to the lens primordium, this outer layer may develop with a well-defined neuroretinal layer and a pigmented layer into a complete retina rather than an RPE (Mikami, 1939). does not form (Holtfreter, 1939; Hyer et al., 1998). Even These and many other observations (Pittack et al., 1997; Hyer though these tissue interactions have long been noted and et al., 1998) suggest that the neuroepithelium of the optic characterized extensively, it remains a challenge to sort out the vesicle is initially bipotential and that its separation into NR molecular mechanisms responsible for them. In particular, and RPE domains is mediated by extrinsic factors that emanate much needs to be learned about the nature of the relevant from the surface ectoderm. signaling molecules and how the cells interpret them to develop Among the factors potentially responsible for this effect, into the eye’s many distinct structures. fibroblast growth factors (FGFs) are prime candidates. Both 3582 M.-T. T. Nguyen and H. Arnheiter FGF1 and FGF2 are expressed in the surface ectoderm (de regulating the expression of Mitf. The results suggest a model Longh and McAvoy, 1993; Pittack et al., 1997) and their in which the initial coexpression of transcription factors marks receptors, FGFR1 and FGFR2, are expressed in the developing undifferentiated, bipotential neuroepithelial precursor cells, optic vesicle (Wanaka et al., 1991; Tcheng et al., 1994). RPE, and the region-specific repression of distinct transcription when exposed to FGF2, develops into NR (Park and factors leads to lineage commitment. Hollenberg, 1989; Pittack et al., 1991, 1997; Guillemot and Cepko, 1992; Zhao et al., 1995), and FGF1 is involved in early optic vesicle patterning in the chick (Hyer et al., 1998). MATERIALS AND METHODS Furthermore, FGFs have well-established roles in patterning of other tissues in both invertebrates and vertebrates. Whether Mice and harvest of embryos FGFs play similar roles in the patterning of the mammalian C57BL/6J embryos were used as Mitf wild-type controls. Mitf mutant optic vesicle, however, remains unknown. Neither FGF1 or embryos were of the genotypes Mitfvga−9/vga9, Mitfmi-ew/mi-ew (eyeless- FGF2 knockout mice nor FGF1/FGF2 double knockout mice white) and MitfMi-wh/Mi-wh (white), whose molecular lesions and have overt eye defects (Dono et al., 1998; Ortega et al., 1998; genetic backgrounds have been described (Hodgkinson et al., 1993; Miller et al., 2000). Thus, in the mouse, FGFs may either have Hemesath et al., 1994; Steingrímsson et al., 1994; Nakayama et al., redundant functions or may collectively be unimportant for 1998). For timed pregnancies, the noon when a vaginal plug was found was defined as embryonic day 0.5 (E0.5). In embryos younger cell-fate decisions in the optic vesicle. than E10.5, somite numbers were counted for accurate staging. Much as determination of the nature of the relevant signaling molecules is crucial to our understanding of eye development, Optic vesicle explant culture and manipulations so is identification of the cell-intrinsic factors, including Embryos were harvested at E9-9.5 in Hepes-buffered DMEM particular transcription factors, through which these signaling supplemented with 10% fetal bovine serum (FBS). The head bands molecules may act. A multitude of transcription factors containing the optic vesicles were dissected and cultured in 10% FBS- specifically involved in the various developmental steps of eye supplemented UltraCulture medium (BioWhittaker) on floating 0.45 formation have recently been identified from spontaneous and µm Nucleopore membranes (Corning #110607) coated with 10 ng/ml poly-D-Lysine (Sigma). Heparin-coated acrylic beads (125-200 µm induced mutations, predominantly in mice. For instance, the µ homeodomain protein RX is needed for optic vesicle formation diameter, Sigma H5263) were soaked in 5 l of 1 mg/ml of human recombinant FGF1, FGF2, murine recombinant EGF (all from Gibco) (Mathers et al., 1997), the lim-homeodomain protein LHX2 or bovine serum albumin (BSA, fraction V, Sigma) for 1 hour (Porter et al., 1997) and the paired-domain protein PAX6 (Hill (Niswander et al., 1993) and implanted into specific locations around et al., 1991) are needed for optic cup formation, and the the optic vesicle, as indicated in the text. Removal of the surface homeodomain protein CHX10 controls the growth of the NR ectoderm was done as described (Furuta et al., 1998). For and the differentiation of retinal interneurons (Burmeister et immunolabeling, the cultured explants were fixed in 4% al., 1996). Based on analyses in dissociated cultures, several paraformaldehyde overnight, cryoprotected in sucrose, embedded in transcription factors, including MITF on which the present OCT compound and sectioned at −14°C. study focuses, have been implicated in cell-fate decisions in Tissue preparations for histological analysis and in situ cultures of dissociated optic cups (Mochii et al., 1998a; Holme hybridization et al., 2000), but none so far has been shown to regulate the Embryo preparations, immunolabeling and in situ hybridizations were separation into NR and RPE in the intact optic vesicle. done as described (Hodgkinson et al., 1993; Chan et al., 1995; We have recently demonstrated that the basic-helix- Nakayama et al., 1998). The following mouse probes, all described loop-helix-zipper (bHLH-Zip) transcription factor MITF previously, were used: Mitf (Hodgkinson et al., 1993), Dct (Opdecamp (Hodgkinson et al., 1993; Hughes et al., 1993), in addition et al., 1997), Chx10 (Liu et al., 1994), Crx (Furukawa et al., 1997), to regulating the
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