Axonal Growth and Guidance Defects inFrizzled3Knock-Out Mice: A Comparison of Diffusion Tensor Magnetic Resonance Imaging, Neurofilament Staining, and Genetically Directed Cell Labeling

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Abstract
Previous work has identified axonal outgrowth and/or guidance defects in the brain and spinal cord of prenatalFrizzled3(Fz3)–/–mice. To systematically explore the axonal defects inFz3–/–mice and to compare techniques for the global assessment of axon tracts in the developing mouse, we have analyzed wild-type andFz3–/–brains using (1) diffusion tensor magnetic resonance imaging (μDTI), (2) neurofilament staining, and (3) two genetically directed neuronal labeling methods. Confirming and extending the previous work of Wang et al. (2002), we find that the following structures/tracts are absent or greatly reduced in theFz3–/–brain: the anterior commissure, cerebral peduncle (corticospinal tract), corpus callosum, fornix, internal capsule (thalamocortical and corticothalamic tracts), stria medullaris, stria terminalis, and hippocampal commissure. An aberrant U-shaped fiber bundle immediately caudal to the optic tract connects the left and right sides of theFz3–/–thalamus and likely represents a default pathway for thalamic axons that failed to enter the internal capsule. At embryonic day 18, labeling of cortical pyramidal cells with a yellow fluorescent protein reporter reveals widespread fragmentation of axons with no apparent loss of pyramidal cell bodies. Fragmentation likely represents one stage in the process that normally eliminates stalled or mistargeted axons. This work demonstrates the usefulness of μDTI and genetically directed neuronal labeling for the analysis of nervous system defects in the mouse.