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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    • "Homozygous NDEL1 knockout mice die at early embryonic stages, while brain-specific mutants show severe cortical neuronal migration defects (Sasaki et al., 2005; Shu et al., 2004; Youn et al., 2009 ). Analyses of mature neurons in conditional NDEL1 knockout mice revealed defects in axon and dendrite morphology and aberrant axonal enlargement at the AIS (Hippenmeyer et al., 2010). We analyzed the morphological defects in cultured neurons. "
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    ABSTRACT: The development and homeostasis of neurons relies heavily on the selective targeting of vesicles into axon and dendrites. Microtubule-based motor proteins play an important role in polarized transport; however, the sorting mechanism to exclude dendritic cargo from the axon is unclear. We show that the dynein regulator NDEL1 controls somatodendritic cargo transport at the axon initial segment (AIS). NDEL1 localizes to the AIS via an interaction with the scaffold protein Ankyrin-G. Depletion of NDEL1 or its binding partner LIS1 results in both cell-wide and local defects, including the non-polarized trafficking of dendritic cargo through the AIS. We propose a model in which LIS1 is a critical mediator of local NDEL1-based dynein activation at the AIS. By localizing to the AIS, NDEL1 facilitates the reversal of somatodendritic cargos in the proximal axon.
    Full-text · Article · Feb 2016 · Neuron
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    • "4 ; Chen et al . , 2005 ) . They are also expressed in NPCs in VZ , which has led to a debate about the existence of fate - restricted progenitors in Cux2 - or Fezf2 - Cre driver mouse lines ( Franco et al . , 2012 ; Guo et al . , 2013 ) . Although a recent report using the mosaic analysis with double marker ( MADM ) system ( Zong et al . , 2005 ; Hippenmeyer et al . , 2010 ) demonstrated unitary production of deep and superficial layer neurons by individual NPCs ( Gao et al . , 2014 ) , this dispute remains unresolved ."
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    ABSTRACT: Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.
    Preview · Article · Jan 2016 · Frontiers in Neuroscience
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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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