Background The alignment of ipsilaterally and contralaterally projecting retinal axons that view the same part of visual space is fundamental to binocular vision. While much progress has been made regarding the mechanisms which regulate contralateral topography, very little is known of the mechanisms which regulate the mapping of ipsilateral axons such that they align with their contralateral counterparts. Results Using the advantageous model provided by the mouse retinocollicular pathway, we have performed anterograde tracing experiments which demonstrate that ipsilateral retinal axons begin to form terminal zones (TZs) in the superior colliculus (SC), within the first few postnatal days. These appear mature by postnatal day 11. Importantly, TZs formed by ipsilaterally-projecting retinal axons are spatially offset from those of contralaterally-projecting axons arising from the same retinotopic location from the outset. This pattern is consistent with that required for adult visuotopy. We further demonstrate that a member of the Ten-m/Odz/Teneurin family of homophilic transmembrane glycoproteins, Ten-m3, is an essential regulator of ipsilateral retinocollicular topography. Ten-m3 mRNA is expressed in a high-medial to low-lateral gradient in the developing SC. This corresponds topographically with its high-ventral to low-dorsal retinal gradient. In Ten-m3 knockout mice, contralateral ventrotemporal axons appropriately target rostromedial SC, whereas ipsilateral axons exhibit dramatic targeting errors along both the mediolateral and rostrocaudal axes of the SC, with a caudal shift of the primary TZ, as well as the formation of secondary, caudolaterally displaced TZs. In addition to these dramatic ipsilateral-specific mapping errors, both contralateral and ipsilateral retinocollicular TZs exhibit more subtle changes in morphology. Conclusions We conclude that important aspects of adult visuotopy are established via the differential sensitivity of ipsilateral and contralateral axons to intrinsic guidance cues. Further, we show that Ten-m3 plays a critical role in this process and is particularly important for the mapping of the ipsilateral retinocollicular pathway.
References
[1]
Drager UC, Olsen JF (1980) Origins of crossed and uncrossed retinal projections in pigmented and albino mice. J Comp Neurol 191: 383–412.
[2]
Hindges R, McLaughlin T, Genoud N, Henkemeyer M, O'Leary DD (2002) EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 35: 475–487.
[3]
Brown A, Yates PA, Burrola P, Ortuno D, Vaidya A, et al. (2000) Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102: 77–88.
[4]
Feldheim DA, Kim YI, Bergemann AD, Frisen J, Barbacid M, et al. (2000) Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25: 563–574.
[5]
Frisen J, Yates PA, McLaughlin T, Friedman GC, O'Leary DD, et al. (1998) Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20: 235–243.
[6]
Rashid T, Upton AL, Blentic A, Ciossek T, Knoll B, et al. (2005) Opposing gradients of ephrin-As and EphA7 in the superior colliculus are essential for topographic mapping in the mammalian visual system. Neuron 47: 57–69.
[7]
McLaughlin T, Hindges R, Yates PA, O'Leary DD (2003) Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping. Development 130: 2407–2418.
[8]
Plas DT, Dhande OS, Lopez JE, Murali D, Thaller C, et al. (2008) Bone morphogenetic proteins, eye patterning, and retinocollicular map formation in the mouse. J Neurosci 28: 7057–7067.
[9]
Schmitt AM, Shi J, Wolf AM, Lu CC, King LA, et al. (2006) Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 439: 31–37.
[10]
Leamey CA, Van Wart A, Sur M (2009) Intrinsic patterning and experience-dependent mechanisms that generate eye-specific projections and binocular circuits in the visual pathway. Curr Opin Neurobiol 19: 181–187.
[11]
Godement P, Salaun J, Imbert M (1984) Prenatal and postnatal development of retinogeniculate and retinocollicular projections in the mouse. J Comp Neurol 230: 552–575.
[12]
Wu HH, Cork RJ, Mize RR (2000) Normal development of the ipsilateral retinocollicular pathway and its disruption in double endothelial and neuronal nitric oxide synthase gene knockout mice. J Comp Neurol 426: 651–665.
[13]
Wu HH, Cork RJ, Huang PL, Shuman DL, Mize RR (2000) Refinement of the ipsilateral retinocollicular projection is disrupted in double endothelial and neuronal nitric oxide synthase gene knockout mice. Developmental Brain Research 120: 105–111.
[14]
Haustead DJ, Lukehurst SS, Clutton GT, Bartlett CA, Dunlop SA, et al. (2008) Functional topography and integration of the contralateral and ipsilateral retinocollicular projections of ephrin-A？/？ mice. J Neurosci 28: 7376–7386.
[15]
Pfeiffenberger C, Cutforth T, Woods G, Yamada J, Renteria RC, et al. (2005) Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping. Nat Neurosci 8: 1022–1027.
[16]
Feng K, Zhou XH, Oohashi T, Morgelin M, Lustig A, et al. (2002) All four members of the Ten-m/Odz family of transmembrane proteins form dimers. J Biol Chem 277: 26128–26135.
[17]
Oohashi T, Zhou XH, Feng K, Richter B, Morgelin M, et al. (1999) Mouse ten-m/Odz is a new family of dimeric type II transmembrane proteins expressed in many tissues. J Cell Biol 145: 563–577.
[18]
Kenzelmann D, Chiquet-Ehrismann R, Leachman NT, Tucker RP (2008) Teneurin-1 is expressed in interconnected regions of the developing brain and is processed in vivo. BMC Dev Biol 8
[19]
Leamey CA, Glendining KA, Kreiman G, Kang ND, Wang KH, et al. (2008) Differential Gene Expression between Sensory Neocortical Areas: Potential Roles for Ten_m3 and Bcl6 in Patterning Visual and Somatosensory Pathways. Cereb Cortex 18: 53–66.
[20]
Li H, Bishop KM, O'Leary DD (2006) Potential target genes of EMX2 include Odz/Ten-M and other gene families with implications for cortical patterning. Mol Cell Neurosci 33: 136–149.
[21]
Rubin BP, Tucker RP, Brown-Luedi M, Martin D, Chiquet-Ehrismann R (2002) Teneurin 2 is expressed by the neurons of the thalamofugal visual system in situ and promotes homophilic cell-cell adhesion in vitro. Development 129: 4697–4705.
[22]
Zhou XH, Brandau O, Feng K, Oohashi T, Ninomiya Y, et al. (2003) The murine Ten-m/Odz genes show distinct but overlapping expression patterns during development and in adult brain. Gene Expr Patterns 3: 397–405.
[23]
Leamey CA, Merlin S, Lattouf P, Sawatari A, Zhou X, et al. (2007) Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision. PLoS Biology 5: 2077–2092.
[24]
Young TR, Leamey CA (2009) Teneurins: important regulators of neural circuitry. Int J Biochem Cell Biol 41: 990–993.
[25]
Zheng L, Michelson Y, Freger V, Avraham Z, Venken KJT, et al. (2011) Drosophila Ten-m and Filamen affect motor neuron growth cone guidance. PLoS One 6: e22956.
[26]
Hong W, Mosca TJ, Luo L (2012) Teneurins instruct synaptic partner matching in an olfactory map. Nature 484: 201–207.
[27]
Mosca TJ, Hong W, Dani VS, Favaloro V, Luo L (2012) Trans-synaptic teneurin signaling in neuromuscular synapse organization and target choice. Nature 484: 237–241.
[28]
Merlin S, Horng S, Marotte LR, Sur M, Sawatari A, et al. (2012) Deletion of Ten-m3 induces the formation of ocular dominance columns in mice. Cereb Cortex
[29]
Drager UC, Hubel DH (1975) Responses to visual stimulation and relationship between visual, auditory, and somatosensory inputs in mouse superior colliculus. J Neurophysiol 38: 690–713.
[30]
Pequignot MO, Provost AC, Salle S, Taupin P, Sainton KM, et al. (2003) Major role of BAX in apoptosis during retinal development and in establishment of a functional postnatal retina. Dev Dyn 228: 231–238.
[31]
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.
[32]
LaVail JH, Nixon RA, Sidman RL (1978) Genetic control of retinal ganglion cell projections. J Comp Neurol 182: 399–421.
[33]
Cang J, Wang L, Stryker MP, Feldheim DA (2008) Roles of ephrin-as and structured activity in the development of functional maps in the superior colliculus. J Neurosci 28: 11015–11023.
[34]
Pfeiffenberger C, Yamada J, Feldheim DA (2006) Ephrin-As and patterned retinal activity act together in the development of topographic maps in the primary visual system. J Neurosci 26: 12873–12884.
Upton AL, Ravary A, Salichon N, Moessner R, Lesch K-P, et al. (2002) Lack of 5HT1B receptor and serotonin transporter have different effects on the segregation of axons in the lateral geniculate nucleus compared to the superior colliculus. Neuroscience 111: 597–610.
[37]
Reese BE (1986) The topography of expanded uncrossed retinal projections following neonatal enucleation of one eye: differing effects in dorsal lateral geniculate nucleus and superior colliculus. J Comp Neurol 250: 8–32.
[38]
Dhande OS, Hua EW, Guh E, Yeh J, Bhatt S, et al. (2011) Development of single retinofugal axons arbors in normal and b2 knock-out mice. J Neurosci 31: 3384–3399.
[39]
Simon DK, O'Leary DD (1992) Development of topographic order in the mammalian retinocollicular projection. J Neurosci 12: 1212–1232.
[40]
Herrera E, Brown L, Aruga J, Rachel RA, Dolen G, et al. (2003) Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 114: 545–557.
[41]
Williams SE, Mann F, Erskine L, Sakurai T, Wei S, et al. (2003) Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 39: 919–935.
[42]
Winters JJ, Ferguson CJ, Lenk GM, Giger-Mateeva VI, Shrager P, et al. (2011) Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P2 phosphatase Fig4. Journal of Neuroscience 31: 17736–17751.
[43]
Sperry RW (1963) Chemoaffinity in the Orderly Growth of Nerve Fiber Patterns and Connections. Proc Natl Acad Sci U S A 50: 703–710.
[44]
Thakar S, Chenaux G, Henkemeyer M (2011) Critical roles for EphB and ephrin-B bi-directional singaling in retinocollicular mapping. Nature Commum 2: 431.
[45]
Garcia-Frigola C, Carreres MI, Vegar C, Herrera E (2008) Zic2 promotes axonal divergence at the optic chiasm by EphB1-dependent andd independent mechanisms. Development 135: 1833–1841.
[46]
Lee R, Petros TJ, Mason CA (2008) Zic2 regulates retinal ganglion cell axon avoidance of ephrinB2 through inducing expression of the guidance receptor EphB1. J Neurosci 28: 5910–5919.
[47]
Petros TJ, Shrestha BR, Mason C (2009) Specificity and sufficiency of EphB1 in driving the ipsilateral retinal projection. J Neurosci 29: 3463–3474.
[48]
Bagutti C, Forro G, Ferralli J, Rubin B, Chiquet-Ehrismann R (2003) The intracellular domain of teneurin-2 has a nuclear function and represses zic-1-mediated transcription. J Cell Sci 116: 2957–2966.
[49]
Nunes SM, Ferralli J, Choi K, Brown-Luedi M, Minet AD, et al. (2005) The intracellular domain of teneurin-1 interacts with MBD1 and CAP/ponsin resulting in subcellular codistribution and translocation to the nuclear matrix. Exp Cell Res 305: 122–132.
[50]
Tucker RP, Beckmann J, Leachman NT, Scholer J, Chiquet-Ehrismann R (2012) Phylogenetic analysis of the teneurins: conserved features and premetazoan ancestry. Mol Biol Evol 29: 1019–1029.
[51]
Feldheim DA, Nakamoto M, Osterfield M, Gale NW, DeChiara TM, et al. (2004) Loss-of-function analysis of EphA receptors in retinotectal mapping. J Neurosci 24: 2542–2550.
[52]
Culican SM, Bloom AJ, Weiner JA, DiAntonio A (2009) Phr1 regulates retinogeniculate targeting independent of activity and ephrin-A signalling. Mol Cell Neurosci 41: 304–312.
[53]
Nicol X, Voyatzis S, Muzerelle A, Narboux-Neme N, Sudhof TC, et al. (2007) cAMP oscillations and retinal activity are permissive for ephrin signaling during the establishment of the retinotopic map. Nat Neurosci 10: 340–347.
[54]
McLaughlin T, Torborg CL, Feller MB, O'Leary DD (2003) Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40: 1147–1160.
[55]
Zhang J, Ackman JB, Xu H-P, Crair MC (2012) Visual map development depends on the temporal pattern of binocular activity in mice. Nat Neurosci 15: 298–307.
