Human Mutations in NDE1 Cause Extreme Microcephaly with Lissencephaly

Abstract

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…The treatments specifically caused retarded cilia disassembly, long cilia, premature differentiation of NPCs, accompanied by reduced cell cycle progression, suggesting that mutations in these genes might underlie NPC depletion resulting in microcephaly (Fig 5A–D). A mutation in Nde‐1 causes microcephaly for which the underlying mechanism remains unclear (Alkuraya et al , 2011). Together, these data suggest that cilia disassembly, cell cycle progression, and neuronal differentiation are causally related to each other.…”

“…Recent studies have uncovered that the proper timing of cilium disassembly mediated by Nde‐1 and TcTex‐1 is critically regulated during cell cycle (Kim et al , 2011; Li et al , 2011; Maskey et al , 2015). Interestingly, mutations in Nde‐1 and microtubule and kinetochore components causing microcephaly and ciliary defects highlight a possible role for the cilium in regulating NPCs to control the number of neurons generated during brain development (Alkuraya et al , 2011; Hu et al , 2014; Waters et al , 2015). However, the biological significance of these spatiotemporally interlinked processes namely cilium disassembly, cell cycle re‐entry and neural progenitor cells (NPCs) differentiation, and the molecular mechanisms linking these cellular events together remain unclear.…”

Neuronal stem cells in the central nervous system and in human diseases

“…In mouse models, ASPM has been shown to be involved in maintaining symmetric divisions of RG cells and in completing cytokinesis (Kouprina et al, 2005;Higgins et al, 2010). Mutation in Nde1, a centrosomal gene, is the cause of a disease called microlissencephaly, which is characterized by extreme microcephaly and grossly simplified cortical gyral structure (Alkuraya et al, 2011). In mice with Nde1 knocking out, RG cells exhibit dramatic defects in mitotic progression, orientation, and chromosome localization, as well as neuronal cell fate determination.…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…Microdeletions encompassing the human NDE1 gene have been to be one of the risk factors for microcephaly, mental retardation, and epilepsy (Hannes et al 2009). Furthermore, mutations in NDE1 result in extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly (Alkuraya et al 2011;Bakircioglu et al 2011). Mutated NDE1 proteins were found to be unstable, incapable of binding cytoplasmic dynein, and did not localize properly to the centrosome.…”

“…In humans, mutations in NDE1 result in severe microcephaly (Alkuraya et al 2011;Bakircioglu et al 2011). Double knockout of Nde1 and Lis1 resulted in a marked reduction in brain size (80% decrease).…”