The structure of the coiled-coil domain of Ndel1 and the basis of its interaction with Lis1, the causal protein of Miller-Dieker lissencephaly.
ABSTRACT Ndel1 and Nde1 are homologous and evolutionarily conserved proteins, with critical roles in cell division, neuronal migration, and other physiological phenomena. These functions are dependent on their interactions with the retrograde microtubule motor dynein and with its regulator Lis1--a product of the causal gene for isolated lissencephaly sequence (ILS) and Miller-Dieker lissencephaly. The molecular basis of the interactions of Ndel1 and Nde1 with Lis1 is not known. Here, we present a crystallographic study of two fragments of the coiled-coil domain of Ndel1, one of which reveals contiguous high-quality electron density for residues 10-166, the longest such structure reported by X-ray diffraction at high resolution. Together with complementary solution studies, our structures reveal how the Ndel1 coiled coil forms a stable parallel homodimer and suggest mechanisms by which the Lis1-interacting domain can be regulated to maintain a conformation in which two supercoiled alpha helices cooperatively bind to a Lis1 homodimer.
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ABSTRACT: Nde1 (red) is localised to the GFAP-positive (green) stem cell of the subventricular zone of the lateral ventricle, and its overexpression in neural stem cells promotes neuronal differentiation while inhibiting astroglial differentiation.Figure optionsDownload full-size imageDownload high-quality image (18 K)Download as PowerPoint slideNeuroscience 01/2014; 271:119–136. · 3.33 Impact Factor
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ABSTRACT: Cellular and Molecular Control of Neuronal Migration provides an up-to-date collection of reviews on the molecular and cellular principles of neuronal migration in the mammalian brain. Over the last decades a rich catalogue of signaling molecules controlling neuronal migration has been compiled, and within this book an international panel of experts provides up-to-date discussions of the state of knowledge how these distinct signaling pathways regulate various aspects of neuronal migration. This book introduces the reader to the latest discoveries and concepts of neuronal migration enabled through the application of most sophisticated methods and cutting edge experimental approaches. Cellular and Molecular Control of Neuronal Migration also provides an update on the underlying cellular and molecular basis of neurodevelopmental migration disorders in human patients for all interested neuroscientists and clinicians.Advances in Experimental Medicine and Biology, Vol 800 01/2014; Springer Science+Business Media., ISBN: 978-94-007-7687-6
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ABSTRACT: Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.05/2014; 3(6). DOI:10.1242/bio.20147807