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To explore the physiological functions of endothelin-2 (ET-2), we generated gene-targeted mouse models. Global Et2 knockout mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2009.05.565 Byline: Ted Erclik (a)(b), Volker Hartenstein (c), Roderick R. McInnes (a)(b), Howard D. Lipshitz (a)(b) Keywords: Eye evolution; Visual system neuron; Cell-type homology; Vsx; Rhabdomeric and ciliary photoreceptors; Vertebrate retina; Compound eye; Optic lobe; Drosophila Abstract: Based on differences in morphology, photoreceptor-type usage and lens composition it has been proposed that complex eyes have evolved independently many times. The remarkable observation that different eye types rely on a conserved network of genes (including Pax6/eyeless) for their formation has led to the revised proposal that disparate complex eye types have evolved from a shared and simpler prototype. Did this ancestral eye already contain the neural circuitry required for image processing? And what were the evolutionary events that led to the formation of complex visual systems, such as those found in vertebrates and insects? The recent identification of unexpected cell-type homologies between neurons in the vertebrate and Drosophila visual systems has led to two proposed models for the evolution of complex visual systems from a simple prototype. The first, as an extension of the finding that the neurons of the vertebrate retina share homologies with both insect (rhabdomeric) and vertebrate (ciliary) photoreceptor cell types, suggests that the vertebrate retina is a composite structure, made up of neurons that have evolved from two spatially separate ancestral photoreceptor populations. The second model, based largely on the conserved role for the Vsx homeobox genes in photoreceptor-target neuron development, suggests that the last common ancestor of vertebrates and flies already possessed a relatively sophisticated visual system that contained a mixture of rhabdomeric and ciliary photoreceptors as well as their first- and second-order target neurons. The vertebrate retina and fly visual system would have subsequently evolved by elaborating on this ancestral neural circuit. Here we present evidence for these two cell-type homology-based models and discuss their implications. Author Affiliation: (a) Program in Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, TMDT Building, 101 College Street, Toronto, Ontario, Canada M5G 1L7 (b) Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 (c) Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, 621 Charles E. Young Drive South, Los Angeles, CA 90095, USA Article History: Received 28 April 2009; Revised 17 May 2009; Accepted 19 May 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.09.035 Byline: Begona de Velasco (a), Ted Erclik (b)(c), Diana Shy (a), Joey Sclafani (a), Howard Lipshitz (b)(c), Roderick McInnes (b)(c), Volker Hartenstein (a) Keywords: Drosophila; Embryo; Pars intercerebralis; Neuroendocrine; Brain; Dchx Abstract: The central neuroendocrine system in the Drosophila brain includes two centers, the pars intercerebralis (PI) and pars lateralis (PL). The PI and PL contain neurosecretory cells (NSCs) which project their axons to the ring gland, a complex of peripheral endocrine glands flanking the aorta. We present here a developmental and genetic study of the PI and PL. The PI and PL are derived from adjacent neurectodermal placodes in the dorso-medial head. The placodes invaginate during late embryogenesis and become attached to the brain primordium. The PI placode and its derivatives express the homeobox gene Dchx1 and can be followed until the late pupal stage. NSCs labeled by the expression of Drosophila insulin-like peptide (Dilp), FMRF, and myomodulin form part of the Dchx1 expressing PI domain. NSCs of the PL can be followed throughout development by their expression of the adhesion molecule FasII. Decapentaplegic (Dpp), secreted along the dorsal midline of the early embryo, inhibits the formation of the PI and PL placodes; loss of the signal results in an unpaired, enlarged placodeal ectoderm. The other early activated signaling pathway, EGFR, is positively required for the maintenance of the PI placode. Of the dorso-medially expressed head gap genes, only tailless (tll) is required for the specification of the PI. Absence of the corpora cardiaca, the endocrine gland innervated by neurosecretory cells of the PI and PL, does not affect the formation of the PI/PL, indicating that inductive stimuli from their target tissue are not essential for early PI/PL development. Author Affiliation: (a) Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA (b) Program in Developmental Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 (c) Department of Molecular and Medical Genetics, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Article History: Received 14 June 2006; Revised 19 September 2006; Accepted 20 September 2006

In the mouse retina, at least ten distinct types of bipolar interneurons are involved in the transmission of visual signals from photoreceptors to ganglion cells. How bipolar interneuron diversity is generated during retinal development is poorly understood. Here, we show that Irx5, a member of the Iroquois homeobox gene family, is expressed in developing bipolar cells starting at postnatal day 5 and is localized to a subset of cone bipolar cells in the mature mouse retina. In Irx5-deficient mice, defects were observed in the expression of some, but not all, immunohistological markers that define mature Type 2 and Type 3 OFF cone bipolar cells, indicating a role for Irx5 in bipolar cell differentiation. The differentiation of these two bipolar cell types has previously been shown to require the homeodomain-CVC transcription factor, Vsx1. However, the defects observed in Irx5-deficient retinas do not coincide with a reduction of Vsx1 expression, and conversely, the expression of Irx5 in cone bipolar cells does not require the presence of a functional Vsxl allele. These results indicate that there are at least two distinct genetic pathways (Irx5-dependent and Vsx1-dependent) regulating the development of Type 2 and Type 3 cone bipolar cells. Keywords: Irx5; Homeobox gene; Ganglion cells; Cone bipolar cells; Retina; Differentiation; Vsx1

This study identifies and characterizes retinal stem cells (RSCs) in early postnatal to seventh-decade human eyes. Different subregions of human eyes were dissociated and cultured by using a clonal sphere-forming assay. The stem cells were derived only from the pars plicata and pars plana of the retinal ciliary margin, at a frequency of [approximately equal to] 1:500. To test for long-term self-renewal, both the sphere assay and monolayer passaging were used. By using the single sphere passaging assay, primary spheres were dissociated and replated, and individual spheres demonstrated 100% self-renewal, with single spheres giving rise to one or more new spheres in each subsequent passage. The clonal retinal spheres were plated under differentiation conditions to assay the differentiation potential of their progeny, The spheres were produced all of the different retinal cell types, demonstrating multipotentiality. Therefore, the human eye contains a small population of cells ([approximately equal to] 10,000 cells per eye) that have retinal stem-cell characteristics (proliferation, self-renewal, and multipotentiality). To test the in vivo potential of the stem cells and their progeny, we transplanted dissociated human retinal sphere cells, containing both stem cells and progenitors, into the eyes of postnatal day 1 NOD/SCID mice and embryonic chick eyes. The progeny of the R5Cs were able to survive, migrate, integrate, and differentiate into the neural retina, especially as photoreceptors. Their facile isolation, integration, and differentiation suggest that human RSCs eventually may be valuable in treating human retinal diseases.

Author(s): Geoff Clarke [1, 2]; Richard A. Collins [2]; Blair R. Leavitt [3]; David F. Andrews [4]; Michael R. Hayden [3]; Charles J. Lumsden [5]; Roderick R. McInnes [1, 2, [...]

The range of clinical phenotypes associated with mutations in the cone-rod homeobox gene CRX (ital), a photoreceptor transcription-factor gene, are discussed. CRX (ital) mutations are perhaps associated with clinical pheotypes that include progressive diseases such as cone-rod dystrophy or retinitis pigmentosa and congenital retinal dystrophy (Leber).