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ScienceWeek
DEVELOPMENTAL NEUROBIOLOGY: ON AXON GUIDANCE
The following points are made by Sarah Guthrie (Current Biology 2004 14:R632):
1) The central nervous system develops as an axon scaffold arranged fairly symmetrically around a ventral midline. As axons grow, they maintain strict relationships to the midline in order to form correct pathways and functional connections. Some axons grow either away from or parallel to the midline, and never cross. Other axons cross the midline once, forming a commissure, and then continue to grow on the other side without recrossing. In humans and other mammals, many major axon tracts have crossed projections. These include the corticospinal tract, which descends from the cerebral cortex, crosses the midline in the brainstem and innervates motor neurons in the brainstem and spinal cord. Two large sensory tracts conveying information from the periphery also cross the midline as they ascend via the spinal cord to the brain. The dorsal column-medial lemniscus pathway crosses within the brainstem, while the spinothalamic tract contains commissural neurons which send axons across the midline at spinal levels.
2) A very similar projection pattern is seen in the fruitfly Drosophila, and many salient features of midline guidance appear to be conserved. For example, in both vertebrates and invertebrates, the attractant protein netrin serves to guide commissural axons towards the midline [1]. In Drosophila, axonal projections away from the midline depend on the presence at the midline of the repellent molecule Slit, which binds axonal Robo receptors [2,3]. As they approach the midline, axons are attracted by netrin, and express only a low level of Robo [4]. Commissureless (Comm) protein at the midline acts to keep Robo receptors localized cytoplasmically, away from the cell surface [5]. When axons cross the midline this inhibition ceases, allowing Robo to appear on cell surfaces and mediate repulsion. This mechanism ensures that axons are not repelled prematurely by the midline, which would result in an absence of crossing.
3) This web of interactions has been a prototype for those interested in studying midline guidance in vertebrates. The discovery of a number of vertebrate Robo and Slits, in species including rodents and humans, has sparked intense research activity to understand the role of Robo-Slit signalling in vertebrates. While two of the vertebrate Robos -- Robo1 and Robo2 -- are highly similar to the fruitfly Robo1, a third, Robo3/Rig1, is more distantly related. Three vertebrate Slits are widely expressed in the midline of the nervous system, as well as in other regions, while spinal commissural axons express Robos. Recent studies have shown that commissural axons fail to exit the midline in slit1, slit2, slit3 triple mutants, while in vitro data show that commissural axons become insensitive to floor plate attraction and sensitive to Slit-mediated repulsion only after crossing the midline. This modulation of repulsion at the midline is reminiscent of the situation in Drosophila. But are the same mechanisms at work? So far no vertebrate homologues of Comm have been identified.
References (abridged):
1 Varela-Echavarri a, A. and Guthrie, S. (1997). Molecules making waves in axon guidance. Genes Dev. 11, 545-557
2 Kidd, T., Brose, K., Mitchell, K.J., Fetter, R.D., Tessier-Lavigne, M., Goodman, C.S. and Tear, G. (1998). Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205-215
3 Kidd, T., Bland, K.S. and Goodman, C.S. (1999). Slit is the midline repellent for the Robo receptor in Drosophila. Cell 96, 785-794
4 Kidd, T., Russell, C., Goodman, C.S. and Tear, G. (1998). Dosage-sensitive and complementary functions of roundabout and commissureless control axon crossing of the CNS midline. Cell 92, 205-215
5 Keleman, K., Rajagopalan, S., Cleppien, D., Teis, D., Paiha, K., Huber, L.A., Technau, G.M. and Dickson, B.J. (2002). Comm sorts robo to control axon guidance at the Drosophila midline. Cell 110, 415-427
Current Biology http://www.current-biology.com
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MEDICAL BIOLOGY: ON THE NETRIN-1 PROTEIN
The following points are made by E.R. Fearon and K.R. Cho (Nature 2004 431:35):
1) Named from the Sanskrit word for "one who guides", the netrin-1 protein was discovered because of its ability to direct the migration of axons in the developing spinal cord(1,2). The functions of netrin proteins in axon guidance and neural cell migration have consequently received much attention (3). But Mazelin et al(4) make the case that netrin-1 might offer unanticipated guidance for the cancer field as well.
2) Netrins are secreted proteins that act on neural cells through transmembrane receptors of the DCC and UNC5H families (3). DCC stands for "deleted in colorectal carcinomas", and as its name implies, DCC was initially described as a candidate tumour-suppressor gene. In colorectal cancer, a chromosomal region containing DCC is frequently deleted. This is often accompanied by low or absent expression of the DCC protein and, occasionally, by specific DCC mutations(3,5) -- as expected for a tumour-suppressor gene. However, it has been argued that DCC might not actually be a tumour-suppressor gene, but be functioning only in the nervous system. This point of view is based on the fact that the mechanisms underlying reduced or absent DCC expression in most cancers are poorly defined(3,5), and the observation that mice lacking one copy of Dcc do not have an obvious predisposition to tumors.
3) The three UNC5H genes -- UNC5H1, UNC5H2 and UNC5H3 -- are also proposed to be tumour-suppressor genes. But concerns similar to those for DCC could be raised about the evidence that links defects in the UNC5H genes to cancer in humans. Possible mechanisms contributing to the loss of UNC5H gene expression in cancer include deletion or mutation of UNC5H genes, and transcriptional mechanisms. For instance, the UNC5H2 gene is regulated by the p53 tumour-suppressor protein, and p53 function is often defective in cancer.
4) Perhaps the strongest suggestion that DCC and UNC5H are indeed involved in cancer comes from observations that in cultured cells, the DCC and UNC5H proteins promote cell death when netrin-1 is absent but enhance cell survival when netrin-1 is present(3). This behavior is consistent with the hypothesis that DCC and UNC5H belong to a class of cellular receptor called "dependence receptors", which induce programmed cell death unless they are occupied by their ligand. Theoretically, there are two mechanisms by which such receptors might cause cancer: either the ligand is present in excess or in the wrong location, so that inappropriate cell survival is encouraged; or the receptors are inactivated or deleted somehow so that cell death is no longer promoted when there is little or no ligand. The specific mechanisms by which netrin-1 binding to DCC or UNC5H affects cell survival or death remain unknown.
References (abridged):
1. Serafini, T. et al. Cell 78, 409-424 (1994)
2. Kennedy, T. E., Serafini, T., de la Torre, J. R. & Tessier-Lavigne, M. Cell 78, 425-435 (1994)
3. Mehlen, P. & Mazelin, L. Biol. Cell 95, 425-436 (2003)
4. Mazelin, L. et al. Nature 431, 80-84 (2004)
5. Fearon, E. R. et al. Science 247, 49-56 (1990)
Nature http://www.nature.com/nature
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NEUROBIOLOGY: ON AXON TARGETING DURING DEVELOPMENT
The following points are made by C. Geoffrey Woods (Science 2004 304:1455):
1) During fetal development most neurons produce extensions called "axons". These axons deliver output signals from the neuronal cell body, often across great distances, to other target neurons. The signal is passed on by synapses at the end of the axons. It is the exact choice of which neuron an axon connects to that produces the functionally specific neuronal circuits of the brain. But how do countless axons find the correct target neurons with which to form synapses, ensuring normal development and function of the nervous system?
2) The more complex the nervous system of an organism, the greater is the problem. The sheer distances traveled by axons --up to 10^(5) times an axon's diameter -- and the number of potential target neurons are staggering. Furthermore, there is the problem of negotiating the midline of the nervous system. How do axons know if and when they need to cross the midline? And if they do cross the midline, how do they know they must only cross it once? Recent studies have supplied a vital missing piece to this complex puzzle.(1,2)
3) Jen et al (1) describe the rare human disorder, horizontal gaze palsy with progressive scoliosis and hindbrain dysplasia (HGPPS). They demonstrate that in HGPPS patients, two major nerve tracts -- the motor corticospinal tract and the dorsal somatosensory tract -- fail to cross the midline in the hindbrain. This alters the appearance of the HGPPS hindbrain, which the authors call the "midbrain butterfly sign". In addition, the principal control center for horizontal eye movement, the abducens nucleus within the hindbrain, is hypoplastic (underdeveloped) in HGPPS. This explains the finding of limited left and right gaze in these patients. Crucially, Jen et al(1) have now identified the cause of HGPPS: Patients carry mutations in the ROBO3 gene, which encodes an important axon guidance receptor.
4) In a complementary study, Sabatier et al(2) describe the effects of engineering mice to lack the Robo3 gene. Although Robo3-deficient mice die soon after birth (because of a failure to wean), these investigators found that the major neurological defect is the same as in humans with HGPPS: Axons fail to cross the midline. Both human and mouse Robo3 are principally expressed in the fetal hindbrain during development (1-3). The Sabatier et al(2) study details the expression patterns of Robo3 in axons that cross the midline of the developing mouse nervous system. The clinical studies of Jen et al(1) reveal the postnatal consequences of the failure of this developmental process in humans. The human and mouse research together reveals the unexpected finding that Robo3 promotes crossing of the midline by axons.(5)
References (abridged):
1. J. C. Jen et al. Science 304, 1509 (2004)
2. C. Sabatier et al., Cell 117, 157 (2004)
3. L. Camurri, E. Mambetisaeva, V. Sundaresan, Gene Expr. Patterns 4, 99 (2004)
4. K. Wong, X. R. Ren, Cell 107, 209 (2001)
5. H. E. Bulow, O. Hobert, Neuron 41, 723 (2004)
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