Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration

Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA.
Neuron (Impact Factor: 15.05). 11/2010; 68(4):695-709. DOI: 10.1016/j.neuron.2010.09.027
Source: PubMed


Coordinated migration of newly born neurons to their prospective target laminae is a prerequisite for neural circuit assembly in the developing brain. The evolutionarily conserved LIS1/NDEL1 complex is essential for neuronal migration in the mammalian cerebral cortex. The cytoplasmic nature of LIS1 and NDEL1 proteins suggest that they regulate neuronal migration cell autonomously. Here, we extend mosaic analysis with double markers (MADM) to mouse chromosome 11 where Lis1, Ndel1, and 14-3-3ɛ (encoding a LIS1/NDEL1 signaling partner) are located. Analyses of sparse and uniquely labeled mutant cells in mosaic animals reveal distinct cell-autonomous functions for these three genes. Lis1 regulates neuronal migration efficiency in a dose-dependent manner, while Ndel1 is essential for a specific, previously uncharacterized, late step of neuronal migration: entry into the target lamina. Comparisons with previous genetic perturbations of Lis1 and Ndel1 also suggest a surprising degree of cell-nonautonomous function for these proteins in regulating neuronal migration.

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    • "We reasoned that among this diverse mesodermal population, a more specific population destined for the cardiac lineage exists. To test this model, we performed in vivo clonal analysis by generating mosaic mice in which very few Mesp1+ cells were labeled at isolated clonal density via the mosaic analysis with double markers (MADM) system (Zong et al., 2005; Hippenmeyer et al., 2010) (Figure 1B–C). This approach is particularly advantageous because labeling events are rare, labeling is permanent, and one can identify labeled daughter cells (twin spots) based on color (Figure 1—figure supplement 1A). "
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    • "[3]–[5]. Each of these interacting proteins have been implicated in neural development; GSK3β regulation by wnt signaling enhances neural progenitor proliferation [6], mutations in NDEL1 and LIS1 cause neuronal migration defects [7], [8], and the DISC1-PDE4 complex can modulate the NDEL1/LIS1 interactions [3]. Overexpression of several human DISC1 variants associated with neuropsychiatric phenotypes in cell lines in vitro or in embryonic cortical progenitors in vivo fails to stimulate cell proliferation and activate β-catenin activity to the same extent as overexpressing wild-type DISC1 [9]. "
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    • "In an effort to identify the key cellular and molecular determinants that underlie normal brain development, researchers have often turned to inherited conditions in which affected individuals exhibit abnormalities in brain development: for example, children with lissencephaly harbor mutations in the LIS1 gene and are born with a brain malformation characterized by defects in the normal folded architecture of the cortex [12]. Using mouse models of lissencephaly, this brain abnormality (“smooth” cortex) is due to impaired migration of neurons into the developing brain [13, 14]. Similarly, individuals with tuberous sclerosis complex (TSC) develop a wide range of brain pathology, including abnormal collections of neurons (heterotopias), due to a mutation in the TSC1 or TSC2 gene [15]. "
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