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How mitotic cell fate is regulated in the developing mammalian CNS is an important but largely unanswered question. Recently reporting in Neuron, Godin et al. showed that Huntingtin, the protein mutated in Huntington's disease, is required for both cerebral cortical neurogenesis and mitotic spindle function in neural progenitors.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 ( FLN1 ), which encodes an actin-cross-linking phosphoprotein that transduces ligand–receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

The inv(16) chromosomal aberration is found in 10% of the cases with AML. The resultant CBFB-MYH11 fusion gene that plays a key-role in the leukemia development, but for full transformation, additional genetic hits are necessary. We report that the MYH11 gene overlaps with the NDE1 gene. At their 3 prime ends the genes overlap at the genomic, transcript as well as coding level and as a consequence, the inv(16) disrupts NDE1 in addition to CBFB and MYH11 in 90% of CBFB-MYH11 positive cases. To determine the relevance of Nde1 function in hematopoiesis leukemia development, hematopoiesis was studied in Nde1-/− and Nde1+/− mutant mice. A significant percentage of the Nde1 null mutant mice developed a myeloproliferative (MPD) phenotype at 6–12 months of age. This phenotype was observed in 6 out of 15 (40%) Nde1−/− mice, 2 out of 15 (13%) Nde1+/− mice and none of 4 wild type mice. All mice with the MPD phenotype exhibited a profound splenomegaly with spleen sizes ranging from 5 to 20-fold larger than normal wild type controls. Histopathological analysis demonstrated hypercellular bone marrow, effacement of normal splenic architecture with expansion of a myeloid cells, and infiltration of proliferating myeloid cells in various organs . A 10-fold increase in Gr1+/Mac1+ double positive mature myeloid cells in the spleen was confirmed by flow-cytometric analysis. Peripheral blood analyses showed that the white blood cell counts were slightly elevated in Nde1 mutant mice that had not yet developed a MPD phenotype compared to wild type mice. A somewhat higher white blood cell count was observed in Nde1 mutant mice with MPD phenotype. In the Nde1 mutant mice with or without splenomegaly we did not observe an increase in the number of B- and T-cells as measured by flowcytometer using various lymphoid cell surface markers. Based on these data we conclude that loss of Nde1 function and Nde1 haploinsufficiency results in the onset of a MPD phenotype. Earlier studies showed that Nde1 is a centrosomal protein. To test whether Nde1 is involved in spindle pole formation and chromosome segregation, we analyzed the mitotic behaviour of mouse embryo fibroblasts (MEFs). From passage 3 to passage 10, aneuploid metaphases increased much more rapidly in Nde1−/− MEFs than in the wild type controls. In addition, a broader spectrum of abnormal chromosome numbers was seen in Nde1−/− MEFs. Thus, Nde1 deficiency results in chromosomal instability. To study whether the numerical chromosome abnormalities were associated with aberrant spindle formation we stained Nde1−/− MEFs with a monoclonal antibody against tubulin. Multipolar spindles and misassembled spindles were more frequently observed in Nde1−/− MEFs compared to wild type cells. We conclude that the abnormal chromosomal segregation of Nde1−/− MEFs is associated with defective mitotic spindle structure. Since Nde1 is disrupted in the majority of inv(16) positive AML patients and the disruption in mice resulted in genetic instability and the onset of myeloproliferative disease, we suggest that the disruption of Nde1 in inv(16)+ AML may serve as additional genetic defect that contributes to leukemogenesis.