Fiber Order of the Normal and Regenerated Optic Tract of the Frog (Rana Pipiens) HELENE BACH, 1,2 VICTORIA ARANGO, 3 DAVID FELDHEIM, 4,5 JOHN G. FLANAGAN, 4 AND FRANK SCALIA 2 * 1 Program in Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203 2 Department of Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203 3 Department of Neuroscience, New York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, New York 10032 4 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 5 Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064 ABSTRACT In the normal frog, axons from the peripheral retina arising at the temporal pole course superficially in the middle stream of the diencephalic optic tract. Axons from the nasal pole course in two streams running in the opposite margins of the tract, dorsonasal axons ventrally, vent- ronasal axons dorsally. Axons from the dorsal and ventral poles of the retina occupy the intervals between the aforementioned middle and marginal streams. Axons from more central regions of the retina tend to occupy deeper levels of the optic tract. The regenerated optic tract does not regain its normal organization, e.g., axons of peripheral nasal origin are spread out widely over the entire width of the tract. However, axons from the temporal pole of the retina do return approximately to their original location in the middle stream. The concentration of temporal axons in the middle stream of the optic tract after regeneration may now be understood in terms of the expression pattern of the ephrin-A class of receptor tyrosine kinase ligands in the cellular matrix of the optic tract. The ephrin-As, which have a repellent effect on growing temporal retinal axons, are concentrated in and along the margins of the diencephalic optic tract and essentially absent from its middle stream. It is proposed here that peripheral temporal axons may be forced into this middle region by their avoidance of the higher levels of ephrin-A expression in the tract margins. In contrast, the growth pattern of regenerating peripheral nasal axons would not be affected by the ephrin-A gradient in the optic tract. J. Comp. Neurol. 477:43–54, 2004. © 2004 Wiley-Liss, Inc. Indexing terms: leopard frog; EphA/ephrin-A; RAP; LAP; chemoaffinity; topographic organization; retinotectal projection Nerve fibers growing across the retina tend to fascicu- late and remain together as they approach the developing optic nerve head. As a consequence, the arrangement of fibers in the mature optic nerve in many species is more or less orderly. The possibility that the fiber order present in the optic nerve might be maintained in passing through the rest of the optic pathway suggested to some that chemoaffinity mechanisms, such as proposed by Sperry (1963), might not be needed for the development of a retinotopically organized retinotectal projection (Horder and Martin, 1978; Bodick and Leventhal, 1980; Grant and Rubin, 1980). This idea can be referred to as the preorga- nization hypothesis. That is, the order of fiber termina- tions in the tectum is predetermined by the ordering of fibers as they approach the tectum. Among the several Grant sponsor: State University of New York-Health Science Center at Brooklyn (F.S.); Grant sponsor: the National Institutes of Health; Grant number: EY11559 (J.G.F.); Grant sponsor: Klingenstein Fellowship (J.G.F.). *Correspondence to: Frank Scalia, Department of Anatomy and Cell Biology, SUNY-Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203. E-mail: fscalia@downstate.edu Received 23 July 2002; Revised 22 April 2004; Accepted 4 May 2004 DOI 10.1002/cne.20238 Published online in Wiley InterScience (www.interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 477:43–54 (2004) © 2004 WILEY-LISS, INC.