Abstract
The left and right sides of the nervous system communicate via commissural axons that cross the midline during development using evolutionarily conserved molecules. These guidance cues have been particularly well studied in the mammalian spinal cord, but it remains unclear whether these guidance mechanisms for commissural axons are similar in the developing forebrain, in particular for the corpus callosum, the largest and most important commissure for cortical function. Here, we show that Netrin1 initially attracts callosal pioneering axons derived from the cingulate cortex, but surprisingly is not attractive for the neocortical callosal axons that make up the bulk of the projection. Instead, we show that Netrin-deleted in colorectal cancer signaling acts in a fundamentally different manner, to prevent the Slit2-mediated repulsion of precrossing axons thereby allowing them to approach and cross the midline. These results provide the first evidence for how callosal axons integrate multiple guidance cues to navigate the midline.
Keywords:
DCC; Robo1; axon guidance; commissure formation; corpus callosum; cortical development; neocortex; silencing.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Axons / physiology*
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Cells, Cultured
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Cerebral Cortex / cytology
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Coculture Techniques
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Corpus Callosum / physiology*
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DCC Receptor
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Embryo, Mammalian
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Female
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Functional Laterality / genetics
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Functional Laterality / physiology
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Humans
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In Vitro Techniques
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Intercellular Signaling Peptides and Proteins / metabolism*
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Male
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Mice, Inbred C57BL
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Mice, Neurologic Mutants
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Netrin-1
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Pregnancy
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Rats, Wistar
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Roundabout Proteins
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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DCC Receptor
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Dcc protein, mouse
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Intercellular Signaling Peptides and Proteins
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NTN1 protein, human
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Nerve Growth Factors
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Nerve Tissue Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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Tumor Suppressor Proteins
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Netrin-1
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Slit homolog 2 protein