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Floor Plate and Netrin-1 Are Involved in the Migration and Survival of Inferior Olivary Neurons

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Floor Plate and Netrin-1 Are Involved in the Migration and Survival of Inferior Olivary Neurons The Journal of Neuroscience, June 1, 1999, 19(11):4407–4420 Floor Plate and Netrin-1 Are Involved in the Migration and Survival of Inferior Olivary Neurons Evelyne Bloch-Gallego,1 Fre´de´ ric Ezan,1 Marc Tessier-Lavigne,2 and Constantino Sotelo1 1Institut National de la Sante´ et de la Recherche Me´ dicale U106, Hoˆ pital de la Salpeˆ trie` re, 75013 Paris, France, and 2Howard Hughes Medical Institute, Department of Anatomy, University of California at San Francisco, San Francisco, California 94143 During their circumferential migration, the nuclei of inferior oli- However, axons of the remaining olivary cell bodies located in vary neurons translocate within their axons until they reach the the vicinity of the floor plate still succeed in entering their target, floor plate where they stop, although their axons have already the cerebellum, but they establish an ipsilateral projection in- crossed the midline to project to the contralateral cerebellum. stead of the normal contralateral projection. In vitro experi- Signals released by the floor plate, including netrin-1, have ments involving ablations of the midline show a fusion of the been implicated in promoting axonal growth and chemoattrac- two olivary masses normally located on either side of the tion during axonal pathfinding in different midline crossing sys- ventral midline, suggesting that the floor plate may function as tems. In the present study, we report experiments that strongly a specific stop signal for inferior olivary neurons. These results suggest that the floor plate could also be involved in the establish a requirement for netrin-1 in the migration of inferior migration of inferior olivary neurons. First, we show that the olivary neurons and suggest that it may function as a specific pattern of expression of netrin receptors DCC (for deleted in guidance cue for the initial steps of the migration from the colorectal cancer), neogenin (a DCC-related protein), and mem- rhombic lips and then later in the development of the normal bers of the Unc5 family in wild-type mice is consistent with a crossed projection of the inferior olivary neurons. They also possible role of netrins in directing the migration of precerebel- establish a requirement for netrin-1, either directly or indirectly, lar neurons from the rhombic lips. Second, we have studied for the survival of inferior olivary neurons. mice deficient in netrin-1 production. In these mice, the number of inferior olivary neurons is remarkably decreased. Some of Key words: development; neuronal migration; organotypic them are located ectopically along the migration stream, cultures; in situ hybridization; axonal tracing; carbocyanine; whereas the others are located medioventrally and form an inferior olivary complex; floor plate; netrin-1; Unc-5H receptors; atrophic inferior olivary complex: most subnuclei are missing. DCC receptor; survival Precerebellar neurons are known to follow circumferential mi- through the marginal stream. More importantly, the cell bodies of gration routes. Thus, the pontine nuclei (Altman and Bayer, LRN and ECN neurons cross the midline ventrally at the floor 1987b; Rakic, 1990), the external cuneatus nucleus (ECN), the plate and continue their translocation until reaching their pre- lateral reticular nucleus (LRN), and the inferior olivary nucleus sumptive territories in the contralateral medulla oblongata. In (ION) (Altman and Bayer, 1987a) all migrate from different contrast, olivary somata move up to the floor plate but stop before regions of the alar ventricular zone of the rhombencephalon to crossing the midline; each cell nucleus of the migrating IO neu- their final destinations. The neurons of the ECN, LRN, and IO rons moves through its own leading process, which corresponds to originate from the same neuroepithelium, and their proliferation the future axon, up to the floor plate, where it stops. The arrest time overlaps, although it occurs somewhat earlier for IO neurons of the migration of the soma occurs despite the fact that its axon than for ECN and LRN neurons: in the rat, IO neurons prolif- has previously crossed the midline and reached the contralateral erate on embryonic day 12 (E12) and E13, whereas LRN and inferior cerebellar peduncle, its cerebellar entry. In rat, olivocer- ECN neurons proliferate on E13 and E14 (Altman and Bayer, ebellar axons reach the cerebellar plate at E16 and enter it at E17 1980, 1987a; Bourrat and Sotelo, 1988, 1991). Migration of IO (Wassef et al., 1992), a period coincident with the end of the IO neurons occurs through the submarginal stream (Altman and migration, which lasts from E13 to E17. One of the striking Bayer, 1980, 1987a; Bourrat and Sotelo, 1988, 1991), whereas characteristics of olivary neurons concerns the different behavior other precerebellar neurons, LRN and ECN neurons, migrate of somata and axons during their migration, in relation to the floor plate. These observations suggest that the floor plate con- Received Jan. 15, 1999; revised March 8, 1999; accepted March 11, 1999. tains or releases signals that affect olivary neurons differently This work was partially funded by European Commission Grant ERBBI04-CT96- 0774 and Association pour la Recherche contre le Cancer Grant 9954. We are from other precerebellar neurons. The responses to such signals grateful to Fre´de´ric Roger for technical assistance. We thank Drs. Patricia Gaspar, must be different for the translocation of cell bodies and the Pierre Angaut, and Nicole Dumesnil for critical reading of this manuscript, Charles Duyckaerts for assistance in cellular measurements, and Denis Le Cren for photo- guidance of olivary axons. The molecular cues that direct these graphic work. We also thank Dr. D. S. Latchman for providing the Brn-3.b probe. developmental events remain unknown. Correspondence should be addressed to Evelyne Bloch-Gallego, Institut National The guidance of growing neurites in the nervous system is, at de la Sante´ et de la Recherche Me´dicale U106, Hoˆpital de la Salpeˆtrie`re, 75013 Paris, France. least partly, mediated by diffusible chemoattractants (Ramon y Copyright © 1999 Society for Neuroscience 0270-6474/99/194407-14$05.00/0 Cajal, 1892; Kingsbury, 1920; Tessier-Lavigne et al., 1988) and/or 4408 J. Neurosci., June 1, 1999, 19(11):4407–4420 Bloch-Gallego et al. • Netrin-1 and Inferior Olivary Development chemorepellents (Pini, 1993) secreted by intermediate axonal post-fixed overnight at 4°C in it. Chick embryos up to stage 30 of target cells. In the spinal cord, the circumferential migrations of Hamburger and Hamilton (HH30) were fixed by immersion and perfused when older as described above for mice. Then they were frozen in commissural axons are directed in part by chemoattractants of the isopentane cooled to 255°C with liquid nitrogen. netrin family (Kennedy et al., 1994; Serafini et al., 1994). In The frozen brains were serially sectioned in a cryostat in the frontal or particular, netrin-1, which is expressed in the floor plate, has been sagittal planes. The sections (20 mm thick) were mounted on four parallel shown directly to be required for growth of commissural axons to sets of slides. the floor plate (Serafini et al., 1996). In vertebrates, two families of receptors for netrin-1 have now been reported: members of the In situ hybridizations and combined immunocytochemistry DCC (for deleted in colorectal cancer) family (DCC and neoge- The chick netrin-1 subclone (Serafini et al., 1994) was linearized with EcoRI or XhoI (Pharmacia, Uppsala, Sweden) and transcribed in the nin; Keino-Masu et al., 1996) and the UNC5-H family (Ackerman presence of digoxigenin (Dig)-UTP (Boehringer Mannheim, Mannheim, et al., 1997; Leonardo et al., 1997). DCC is a netrin-binding Germany) using T7 RNA polymerase or T3 RNA polymerase (riboprobe protein expressed by the axons of commissural neurons as they kit; Promega, Madison, WI) to produce the antisense or sense probes, project to the floor plate (Keino-Masu et al., 1996). Mice lacking respectively. The mouse netrin subclone (Serafini et al., 1996) was lin- DCC function (Fazeli et al., 1997) exhibit a phenotype relatively earized with EcoRI or SacI and transcribed in the presence of Dig-UTP using T3 RNA polymerase or T7 RNA polymerase to produce the similar to that of mice carrying a severe hypomorphic allele of antisense or sense probes, respectively. No signal was obtained when netrin-1 (Serafini et al., 1996), with, in each case, severe defects in using the sense probes. The mouse DCC (Keino-Masu et al., 1996) the formation of the anterior commissure, absence of corpus subclone called D78 was linearized with ApaIorKpnI and transcribed in callosum and pontine nuclei, reduction in size of the ventral the presence of Dig-UTP using SP6 or T7 RNA polymerase to produce the antisense or sense probes, respectively. The rat Unc-5H1 probe spinal commissure, and errors in axonal pathfinding of commis- (Leonardo et al., 1997) was linearized with XbaIorKpnI and transcribed sural neurons in the spinal cord. Vertebrate homologs of Caeno- in the presence of DigUTP using or T3 polymerase to produce the rhabditis elegans UNC5 are also netrin-binding proteins; these antisense or sense probes, respectively. The rat Unc-5H2 probe (Leo- include the product of the mouse rostral cerebellar malformation nardo et al., 1997) was linearized with NotIorHincII and transcribed in gene RCM (renamed UNC5H3; Ackerman et al., 1997, Przybor- the presence of Dig-UTP using T7 or T3 RNA polymerase to produce the antisense or sense probes. The mouse Unc-5H3 probe (Leonardo et ski et al., 1998) and of two rat genes, UNC5H1 and UNC5H2 al., 1997) was linearized with BamHI or KpnI and transcribed in the (Leonardo et al., 1997). By homology with the presumed function presence of dig-UTP using T7 or T3 RNA polymerase to produce of C. elegans UNC5 as a repulsive netrin receptor (Culotti and respectively the antisense and sense probes.
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