Brose, N.

Rosenmund, C.

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Neuron, Vol. 24, 763±768, December, 1999, Copyright 1999 by Cell PressPreviewsby catalyzing the removal of iodine from the inner ring.The Metamorphosis AntidoteWhen the function of D3 was inactivated by iopanoicacid (IOPA), a specific inhibitor of the enzyme, the asym-metric growth pattern in response to thyroid hormoneWhat if you woke up one morning and your eyes were was lost, and both dorsal and ventral CMZ grew equally.on the top of your head? You would be confused to see In complementary experiments, they introduced a D3the sky in front of you and would worry that if you took transgene under the control of a ubiquitous or neuron-a step to the rear you would smash into the ground. specific promotor, which resulted in the inhibition of theThis could never happen unless you lived in a Kafka- growth burst in the ventral retina during metamorphosis.esque story and had been transformed into a giant These results clearly show that the expression of D3clawed frog. Xenopus really do experience such a in the dorsal CMZ inactivates thyroid hormone locally,change in the position of their eyes during their Meta- which prevents the cells from responding to the highmorphosis, but they have an antidote to this disorienting level of circulating thyroid hormone during the metamor-morphogenetic movement. phic climax.In Xenopus, the laterally positioned eyes of the filter- The steroid hormones are known to regulate variousfeeding tadpole move dorsally and frontally during meta- aspects of nervous system development, and there aremorphosis, which results in the predatory frog's binocu- several cellular mechanisms to regulate the region-spe-lar overlapping visual field (Grobstein and Comer, 1977; cific responses. The first mechanism, commonly foundGrant and Keating, 1986). Unlike the retina in mammals in other endocrine systems, is the expression of theor birds, the frog retina continues to grow throughout receptor only in target tissues. The second is the expres-life by adding newly born cells to the ciliary marginal sion of different receptor subtypes in each target organ.zone (CMZ) at the periphery (GluÈ cksmann, 1940; Perron A striking example of this strategy is found in insectet al., 1998). It has long been known that retinal growth metamorphosis. In Drosophila, it has been establishedin the ventral CMZ is much greater than in the dorsal that the differential responses to ecdysone, a steroidCMZ during and after metamorphosis (Hollyfield, 1971; hormone that induces metamorphosis in insects, areStraznicky and Tay, 1977; Beach and Jacobson, 1979). regulated by the discrete expression of specific receptorThis asymmetrical growth pattern displaces the ªoldº subtypes (Talbot et al., 1993). The tissues that followretina dorsally and compensates for the dorsal move- the same fate (proliferation, differentiation, cell death)ment of the eyes (see figure). Thus, a particular locus during metamorphosis have the same expression pat-in the ªoldº retina continues to represent a similar loca- terns of ecdysone receptor A and ecdysone receptor B.tion in the space in relation to the body, reducing the The third mechanism, as shown by Marsh-Armstrong etmismatch between the ªinterocularº and ªvisuosomaticº al. in this issue, is the inactivation of the ligand in amap (Grant and Keating, 1986). Thyroid hormone is a region-specific manner. It would be intriguing to knowkey molecule during metamorphosis and is involved in if similar regulatory mechanisms are involved in othera variety of processes, including the generation of an regions of the brain or in other animals.ipsilateral retinal projection that serves binocular vision In addition to the effect on the retinal growth, Marsh-(Hoskins, 1986). Thyroxine can cause the asymmetrical Armstrong et al. showed a reduction in the number ofgrowth pattern precociously in premetamorphic tad-poles, and an inhibitor of thyroid hormone synthesis canblock the differential growth pattern, suggesting thatthyroid hormone is sufficient and necessary for thechanges in retinal growth during metamorphosis (Hos-kins, 1986). However, the molecular mechanism bywhich the hormone elicits differential growth in the dor-sal and ventral CMZ has been an open question, sincethe receptors for thyroid hormone are expressed ubiqui-tously in the nervous system and equally in the dorsaland ventral CMZ (Kawahara et al., 1991). In this issueof Neuron, Marsh-Armstrong et al. (1999) give a finalanswer to this long unsolved problem by analyzing thefunction of D3, an enzyme that inactivates thyroid hor-mone, in the metamorphosing retina.Earlier work from the same lab (Wang and Brown,1993) characterized a number of genes that are inducedImage Constancy in a Metamorphosing Frogin response to thyroid hormone. In the present paper,During metamorphosis, the tadpole retina moves dorsally to the topby screening hormone-responsive genes in the meta-of the frog's head. The ventral growth of the retina (dark shadow)morphosing retina, Marsh-Armstrong et al. found that exceeds dorsal growth and compensates the movement of the eyes.D3 was expressed highly in the dorsal CMZ but not in Consequently, the same region in the retina (asterisk) can receivethe ventral CMZ. D3 is a member of a class of enzymes visual information from an object (fish) that is located ªlateralº tothe body.called deiodinases, which inactivate thyroid hormoneNeuron764ipsilaterally projecting retinal ganglion cells in the D3 the elimination of inappropriate subcortical axon projec-tions.transgenic frog. Since D3 reduces the proliferation inOtx1 is a mammalian homolog of the Drosophila genethe CMZ, it is not clear if D3 overexpression directlyorthodenticle, a homeodomain transcription factor (Si-affects the fate of the ipsilaterally projecting cells or justmeone et al., 1992). Otx1 is expressed in progenitor cellsdecreases the number of ventral ganglion cells gener-in the cortical ventricular zone and in deep layers of theated during metamorphosis. Whichever the case, furthercortex (Frantz et al., 1994). To determine the functionstudy of frog metamorphosis will possibly open a doorof Otx1 in cortical development, Weimann et al. firstto another long-unanswered question, the differentialexamined the pattern of Otx1 protein localization in thedecussation of retinal axons at the chiasm.developing cerebral wall. They found that Otx1 was ex-cluded from the nucleus in ventricular zone cells, butShinichi Nakagawa and William A. Harris was predominantly nuclear in a subset of cortical layerUniversity of Cambridge 5 neurons, suggesting that there is a regulated translo-Department of Anatomy cation of Otx1 into the nucleus during development.Downing Street By combining retrograde labeling from target structuresCambridge CB2 3DY with Otx1 immunofluorescence, they also found that theUnited Kingdom Otx1 protein is present in subcortical, but not callosal,projection neurons.Selected Reading To determine the functional significance of Otx1 ex-pression in cortical neurons, Weimann et al. analyzedBeach, D.H., and Jacobson, M. (1979). J. Comp. Neurol. 183, the consequences of a targeted disruption of Otx1 on603±613.the development of cortical efferent projections. TheGluÈ cksmann, A. (1940). Brit. J. Ophthalmol. 24, 153±178. Otx1 mutant mice were generated by targeting the firstGrant, S., and Keating, M.J. (1986). J. Embryol. Exp. Morphol. 92, and second exons of the Otx1 gene (which include most43±69.of the homeodomain) (Acampora et al., 1996). TheseGrobstein, P., and Comer, C. (1977). Nature 269, 54±56.mice express a truncated Otx1 protein. While it is difficultHollyfield, J.G. (1971). Dev. Biol. 24, 264±286. to know whether the truncated protein retains any Otx1Hoskins, S.G. (1986). J. Neurobiol. 17, 203±229. function, the protein is likely to be functionally compro-Kawahara, A., Baker, B.S., and Tata, J.R. (1991). Development 112, mised since the homeodomain is disrupted, and Otx1933±943. immunoreactivity is lost (Weimann et al., 1999). Some-Marsh-Armstrong, N., Huang, H., Remo, B.F., Liu, T.T., and Brown, what surprisingly, in situ hybridizations using probes toD.D. (1999). Neuron 24, this issue, 871±878.the third exon revealed that transcripts containing thatPerron, M., Kanekar, S., Vetter, M.L., and Harris, W.A. (1998). Dev. exon are expressed in all layers of the cortical plate inBiol. 199, 185±200.the mutant mice. This is in contrast to normal mice, inStraznicky, K., and Tay, D. (1977). J. Embryol. Exp. Morphol. 40,which expression is restricted to the deep cortical lay-175±185.ers, and suggests that the targeted region of Otx1 mightTalbot, W.S., Swyryd, E.A., and Hogness, D.S. (1993). Cell 73, 1323±contain DNA sequences that normally restrict Otx1 ex-1337.pression to deep cortical layers.Wang, Z., and Brown, D.D. (1993). J. Biol. Chem. 268, 16270±16278.Analysis of the Otx1 mutant mice revealed strikingdefects in the patterning of subcortical projections. Ef-ferent projections from the mature visual cortex are nor-mally restricted primarily to the thalamus, superior col-liculus, and pons. In Otx1 mutant mice, these projectionsTranscriptional Control appear normal, but in addition there is extensive innerva-tion of the inferior colliculus and the spinal cord. Sinceof Cortical Connectivityinnervation of the inferior colliculus and spinal cord fromvisual cortex is normally seen early in development butlater is eliminated, the phenotype of the Otx1 mutantThe development of connections in many regions of the mice suggests that Otx1 is required for the elimination ofmammalian brain is characterized by the formation of exuberant axon projections from inappropriate targets.widespread axon projections, followed by elimination It is not clear why visual cortical projections to theof inappropriate axon terminals. For example, layer 5 inferior colliculus and spinal cord are maintained in Otx1neurons in the visual cortex initially extend axons into mutant mice. One possibility is that Otx1 function isthe pons, superior and inferior colliculus, and spinal required for the specification of regional identity in thecord. Later in development, the axonal branches that cortex. Presumptive visual cortical neurons in Otx1 mu-project to the inferior colliculus and spinal cord are elimi- tant mice might retain their projections to inferior collicu-nated, leaving behind the mature projection pattern lus or spinal cord if their identities were switched to(Stanfield et al., 1982; Stanfield and O'Leary, 1985). those of auditory or motor cortex. Regional identity,While such large-scale remodeling of axon terminal however, appears to be unaffected in the Otx1 mutantsfields is important for the establishment of functional as projections from visual cortex to the lateral geniculateconnections, the molecular mechanisms that regulate nucleus develop normally in these mice (Weimann et al.,this process are not well understood. In this issue of 1999). It would be useful to know if other aspects ofNeuron, Weimann and colleagues (1999) provide evi- regional identity (such as innervation from specific thala-mic nuclei) are also normal in Otx1 mutants.dence that the transcription factor Otx1 is required for

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