title: Shh/Boc signaling is required for sustained generation of ipsilateral projecting ganglion cells in the mouse retina.
abstract: Sonic Hedgehog (Shh) signaling is an important determinant of vertebrate retinal ganglion cell (RGC) development. In mice, there are two major RGC populations: (1) the Islet2-expressing contralateral projecting (c)RGCs, which both produce and respond to Shh; and (2) the Zic2-expressing ipsilateral projecting RGCs (iRGCs), which lack Shh expression. In contrast to cRGCs, iRGCs, which are generated in the ventrotemporal crescent (VTC) of the retina, specifically express Boc, a cell adhesion molecule that acts as a high-affinity receptor for Shh. In Boc(-/-) mutant mice, the ipsilateral projection is significantly decreased. Here, we demonstrate that this phenotype results, at least in part, from the misspecification of a proportion of iRGCs. In Boc(-/-) VTC, the number of Zic2-positive RGCs is reduced, whereas more Islet2/Shh-positive RGCs are observed, a phenotype also detected in Zic2 and Foxd1 null embryos. Consistent with this observation, organization of retinal projections at the dorsal lateral geniculate nucleus is altered in Boc(-/-) mice. Analyses of the molecular and cellular consequences of introducing Shh into the developing VTC and Zic2 and Boc into the central retina indicate that Boc expression alone is insufficient to fully activate the ipsilateral program and that Zic2 regulates Shh expression. Taking these data together, we propose that expression of Boc in cells from the VTC is required to sustain Zic2 expression, likely by regulating the levels of Shh signaling from the nearby cRGCs. Zic2, in turn, directly or indirectly, counteracts Shh and Islet2 expression in the VTC and activates the ipsilateral program.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.|CIBER de Enfermedades Raras, Madrid 28049, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Sánchez-Arrones
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.|CIBER de Enfermedades Raras, Madrid 28049, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Nieto-Lopez
authors.affiliation: CIBER de Enfermedades Raras, Madrid 28049, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Camacho
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández de Elche, Alicante 03550, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Carreres
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández de Elche, Alicante 03550, Spain.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Herrera
authors.affiliation: Stanford University, Department Neurology, Stanford, California 94305.
authors.forename: Ami
authors.initials: A
authors.lastname: Okada
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.|CIBER de Enfermedades Raras, Madrid 28049, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
mesh_terms: D000818:Animals; D018274:Electroporation; D025461:Feedback, Physiological / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000172:deficiency; D007839:Functional Laterality / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005829:Geniculate Bodies / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014795:Visual Pathways / Q000502:physiology
chemical_list: C510745:Boc protein, mouse; D051858:Forkhead Transcription Factors; C489562:Foxd1 protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D014157:Transcription Factors; C491811:Zic2 protein, mouse; D049452:Green Fluorescent Proteins