The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein

Abstract

Migration of neurons from proliferative zones to their functional sites is fundamental to the normal development of the central nervous system. Mice homozygous for the spontaneous rostral cerebellar malformation mutation (rcm(s)) or a newly identified transgenic insertion allele (rcm(tg)) exhibit cerebellar and midbrain defects, apparently as a result of abnormal neuronal migration. Laminar structure abnormalities in lateral regions of the rostral cerebellar cortex have been described in homozygous rcm(s) mice. We now demonstrate that the cerebellum of both rcm(s) and rcm(tg) homozygotes is smaller and has fewer folia than in the wild-type, ectopic cerebellar cells are present in midbrain regions by three days after birth, and there are abnormalities in postnatal cerebellar neuronal migration. We have cloned the rcm complementary DNA, which encodes a transmembrane receptor of the immunoglobulin superfamily. The sequence of the rcm protein (Rcm) is highly similar to that of UNC-5, a Caenorhabditis elegans protein that is essential for dorsal guidance of pioneer axons and for the movement of cells away from the netrin ligand, which is encoded by the unc-6 gene. As Rcm is a member of a newly described family of vertebrate homologues of UNC-5 which are netrin-binding proteins, our results indicate that UNC-5-like proteins may have a conserved function in mediating netrin-guided migration.

The expression pattern of nuclear receptors during cerebellar development

“…Furthermore, along the anterior-posterior axis including the ten lobules, the vermis is also divided into the anterior (lobule I to V/VI) and posterior compartment (lobule V/VI to X) (Kuemerle et al, 1997). The existence of this morphological boundary for the anterior and posterior cerebellum is supported by observations of structural abnormalities that are restricted primarily to the anterior or posterior cerebellum lobules in loss of function assays, such as that observed for the Engrailed-2 and BETA2/NeuroD1 genes (Ackerman et al, 1997;Kuemerle et al, 1997;Cho and Tsai, 2006). In conclusion, the profound morphological transformations that occur during development make the cerebellum an extremely useful organ for studying neurogenesis.…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…In neurons, DCC was shown to mediate the attractive activity of netrin-1, in association with A2b. 144,145 UNC5s seem required for netrin-1 repulsive activity, at least in vitro [147][148][149] and this might also require interaction with DCC. 140,150 However, in C. elegans and Drosophila embryo 150 UNC5 could signal independently of DCC.…”

Receptors that mediate cellular dependence

“…It was therefore proposed that the mammalian Unc5H1-3 may function as netrin-1 receptors. 46,47 Subsequent studies suggested that DCC/Unc-40 mediates the chemoattractive effect of netrin-1, whereas Unc5H is involved with the chemorepulsive effect of netrin-1, as an interactor of DCC within the intracytoplasmic region. 43 This notion of attraction/ repulsion, however, did not explain settings in which netrin-1 appears to serve as a chemoattractant for axons that do not express DCC, or in which neurons that express both DCC and Unc5H nonetheless undergo attraction to netrin-1 rather than repulsion by it.…”