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Developmental biology 2008 Lecture 3: Development of the eye Chap. 12 p. 397-401 Chap. 13 p. 436-441 Stine Falsig Pedersen [email protected]/room 527 Dept. of Biology University of Copenhagen Fates of the ectoderm This lecture Previous lecture First lecture Fig. 12.1 2 The vertebrate eye Aqueous humor Cornea Iris + ciliary body Lens Optic nerve Neural retina Pigmented retina 3 The sensory organs of the head develop from interactions between the neural tube and a series of epidermal thickenings formed at the anterior border between the epidermal and neural ectoderm, the cranial sensory placodes. The cranial sensory placodes give rise to the sensory apparatus of nose, ears, and taste receptors, to the lens, and to the glossopharyngeal, facial, and vagal sensory neurons. Fig. 13.11 4 Development of the vertebrate eye Fig. 6.5A-B Mouse day 9-10 The neural tube (presumtive forebrain region) is induced by the chordamesoderm (mostly presumptive notochord) to bulge out and form the optic vesicle. Subsequently: (A) The optic vesicle induces the overlying ectoderm to become the lens placode (B) The lens now induces the optic vesicle to become the optic cup (reciprocal induction) (C) The optic cup differentiates into neural retina (inner) and pigmented retina (outer) 5 Development of the vertebrate eye Fig. 6.5D-E Mouse day 11-13 (D) The lens placode separates from the overlying ectoderm to become the lens vesicle, and the lens cells start to differentiate (E) The lens induces the overlying ectoderm to become the outer layer of the cornea (helped by enzymes from neural crest cells). Retinal ganglion cell axons begin to grow along the inner surface of the retina toward the optic disc, the head of the optic nerve 6 Lens induction is a multistep process with more than one inducer and reciprocal inductive processes Fig. 6.5F 7 Development of the vertebrate eye Fig. 12.26 Mouse ca. day 9-10 Mouse ca. day 11-13 8 Role of the cytoskeleton in lens formation Contraction of the apical F-actin cytoskeleton in the lens placode contributes to lens closure Eye development in stage 15 chick embryo Zolessi & Arruti (2001) BMC Developmental Biology 1:7 9 Transcription factors in lens induction in amphibians - I Fig. 6.4 Otx2 expression is induced in the presumptive lens ectoderm in the late gastrula stage, possibly as a result of signals from the pharyngeal endoderm and heart-forming mesoderm 10 Transcription factors in lens induction in amphibians - II Fig. 6.4 Pax6 makes the presumptive lens ectoderm Signals from the anterior neural plate (including presumptive retina) induce Pax6 competent to be induced (likely by BMP expression in the presumptive lens ectoderm family proteins) by the optic vesicle to express 11 Sox3 and initiate lens formation Induction of the optic vesicle in vertebrates requires at least three transcription factors expressed in the anterior neural plate: Rx1 (of the retinal homeobox genes) Six3 (SIX homeodomain family) Pax6 (paired box and paired-like homeobox gene) • Otx2 upregulates Rx1 • Rx1 is required for continued expression of Six3 and Pax6 in the prospective retina • Six3 is a direct activator of Pax6 These are important, but many more factors contribute to the complete development of the eye! 12 Role of Rx genes in vertebrate retina development Xr1 is the Xenopus Rx1 gene Early Xenopus neurula Newly hatched tadpole Mouse and human blindness due to Rx mutations 13 Pax 6 is widely expressed in the eye in early development mRNA in situ hybridization showing Pax6 expression in the prospective lens ectoderm and the optic cup, and later in lens, retina, and cornea mouse embryo day 10 mouse embryo day 15 Grindley et al (1995) Development 121: 133-142 14 Pax6 acts as a competence factor for lens induction The inductive signal from the optic vesicle is necessary, but not sufficient: Pax6 plays an important role in making the prospective lens ectoderm in which it is expressed competent to be induced by the optic vesicle to form the lens. The lens-inducing factors from the optic vesicle appear to be BMP4 (which leads to Sox2 and Sox3 production) and FGF8 Fig. 6.1 Fig. 6.2 Pax 6 knockout mice lack eyes 15 The essential role of Pax6 in eye development is highly conserved 16 Generation of two eyes Sonic hedgehog from the prechordal plate inhibits Pax6 expression in the center of the embryo, causing the eye field to be split in two. Inactivating mutations of sonic hedgehog cause cyclopism: development of only one eye. Wt and shh-/- mouse embryos Pax6 in Xenopus in ctrl. (C) and with prechordal mesoderm removed (D) Red: Otx2 17 Conversely, loss of eyes in the cavefish Astynanx mexicanus reflects reduced Pax6 expression (caused by upregulation of sonic hedgehog, not shown). 5-somite 18-somite Jeffery (2001) Dev. Biol. 231: 1–12 18 Development of the neural retina - I 2 week mouse ~ 7 week human embryo 19 Development of the neural retina - II Cell division, migration, and differentiation of pluripotent precursor cells of the neural retina germinal layer gives rise to all the cell types of the neural retina. Here shown: photoreceptors, neurons, and glial cells B-galactosidase labeling of retinal precursor cell 20 Development of the neural retina - III The germinal neuroepithelium of the retina is located closest to the lens, in the ganglion cell layer To become retinal neurons, precursor cells must exit from mitosis and migrate out to the correct location Specification of cell fate is thought to occur just after the last mitosis Retinal neurons migrate along the elongated cell bodies and processes of retinal neuroepithelial cells Migration and localization is modulated by specific adhesion molecules (e.g. Cadherins, N-CAM, integrins), and secreted and cell surface guidance cues and extracellular matrix Malicki (2004) Curr. Op. Neurobiol. 14:15–21 21 Development of the lens The inner cells of the lens vesicle elongate and become the lens fibers, which fill up with crystallins and loose their nuclei and organelles, becoming transparent 22 From neural crest Development of the lens, cornea, and iris Cornea develops from neural crest mesenchymal cells Iris (which controls pupil size) and the ciliary body (which forms the aqueous humor) develop from the optic cup Fig. 12.32 Day 13 Day 15 Day 14 Day 15½ 23 Roles of Sox2 and Pax6 in development of the lens Induced in the lens placode by BMP4 secreted from the optic vesicle Fig. 12.32 24 Development of the lens Lens cell division and elongation in the anterior/equatorial zone Crystallin-containing lens fibres 25 8 week old human embryo Development of the cornea and iris The lens induces the overlying ectoderm to form the cornea, the shaping of which requires the aqueous humor. The inner layer of the cornea derives from cranial neural crest cells. The iris (a pigmented muscular tissue responsible for controlling pupil size) develops from the outer rim of the optic cup (i.e., the iris is an ectodermally derived muscle!). 26 Migration of the retinal ganglion neuron axons The axons of retinal ganglion neurons (RGNs) travel through the optic nerve to the optic tectum: the dorsal portion of the midbrain/mesencephalon, mediates reflective responses to visual stimuli (in humans, the corresponding region is the lateral geniculate nucleus). Fig. 13.32 Lateral geniculate nucleus Fig. 22.21 Visual cortex In mammals, most RGNs cross over at the optic chiasm to project contralaterally to the lateral geniculate nucleus, but the ventrotemporal RGNs project ipsilaterally. 27 Forces working on the axon growth cone Laminin/integrin Netrins/DCCs + UNCs EphA7/ephrinA5 semaphorin 1/plexin Modified from Hubert et al (2003) Ann Rev Neurosci 26:509-63 Eph/ephrin Neurotrophins: BDNF, NGF, NT-3, NT-4 semaphorin 3,5/plexin Slit/Robo NB: this is a simplified summary of some important players – whether a given signal is in fact repulsive or attractive is often cell-type specific! 28 Guidance cues direct the growth cone by modulation of actin polymerization and organization Hubert et al (2003) Ann Rev Neurosci 26:509-63 29 Guidance cues direct the growth cone by modulation of actin polymerization and organization Hubert et al (2003) Ann Rev Neurosci 26:509-63 30 Roles of Netrin and semaphorin 5 in directing retinal ganglion neurons through the optic nerve head Netrin (red) from the neuroepithelial cells of the optic nerve head is a chemoattractant for the RGNs and guides them through the optic nerve head (although prior to the entry into the optic nerve head, netrin is a chemorepellant, due to the additional presence of laminin). Semaphorin 5 (green) which is expressed in the perifery of the optic nerve head, is a chemorepellant for the RGNs, and prevents the RGN axons from diverging from their path. Oster et al (2004) Sem. Cell & Dev. Biol. 15:125–136 31 Migration of the retinal ganglion neuron axons Fig. 13.32 32 Slit proteins inhibit axon outgrowth from retinal neurons Slits are secreted proteins which act via the Roundabout (Robo) receptors, and which are generally chemorepellants for axon growth cones Slit proteins in the pre-optic area inhibit outgrowth of the retinal neurons before they reach the optic chiasm R: Retinal explant POA: pre-optic area WT: wildtype MOCK: control Plump et al (2002) Neuron 33:219–232 33 Role of Slit proteins in preventing retinal ganglion neurons from prematurely crossing over before the optic chiasm Plump et al (2002) Neuron 33:219–232 34 Migration of the retinal ganglion neuron axons Fig. 13.32 35 Ventrotemporal RGNs are very sensitive to repulsion by ephrin, and are therefore prevented from crossing at the optic chiasm Ephrin Ephrin B2 is expressed at the midline of the optic chiasm Axon outgrowth from the ventrotemporal (VT) RGNs, which cannot cross the midline (project ipsilaterally), is more strongly prevented by Ephrin B2 than that from dorsotemporal (DT) RGNs, which do cross and project contralaterally, because the VT neurons express high levels of EphB1 receptors Williams et al (2003) Neuron 39:919-35 Migration of the retinal ganglion neuron axons Fig. 13.32 37 Role of Eph/ephrin interactions in the targeting of retinal ganglion neurons the correct position in the optic tectum Once the RGN axons reach the optic tectum (in humans aka superior colliculus), they must target to a specific region: Those coming from the temporal part of the retina go to the rostral/anterior part of the tectum, and those from the nasal part of the retina go to the caudal/posterior part of the tectum. This is achieved in part by a caudal-torostral gradient of ephrins in the tectum, and a temporal-to-nasal gradient of Eph receptors in the RGNs A Wnt3 gradient in the tectum contributes in a similar manner 38 Neurotrophins and neuronal survival in the retina A large fraction – up to 80% - of the retinal neurons must undergo apoptosis during eye development Chick retina TUNEL stained for apoptotic cells Pinon-Duarte et al (2004) Eur J Neurosci 19:1475-84 Postnatal day 7 (P7) rat retinas grown in vitro for 7 days with or without BDNF: retinal neuron and glial survival during development is regulated by BDNF. Mayordomo et al (2003) Eur J Neurosci 18:1744-50 A comparable competition for neurotrophins takes place in the optic tectum (p. 710-12) Essential take-home points I Fig. 6.5F 40 Essential take-home points II Optic vesicle (from neural tube) induces lens from ectoderm, becomes optic cup, then retina, and differentiates into neural and pigmented retina RGN axons grow through optic nerve head, controlled by e.g. netrins and semaphorins Correct crossing/noncrossing at chiasm involves slits and ephrin Targeting involves ephrin gradient at the optic tectum 41 So much for the fates of the ectoderm…….. Fig. 12.1 42 43 Slit-Robo signaling Fernandis & Ganju, Sci STKE 2001 44 Overview of major guidance cues in retinal ganglion guidance Semaphorin 5 Wnt3 45