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Mutations in the microtubule-associated protein Eml1 lead to ectopic progenitors and heterotopia formation during cortical development in mouse and human

ABSTRACT: Neuronal migration disorders such as lissencephaly and subcortical band heterotopia (SBH) are associated with epilepsy and intellectual disability. Doublecortin (DCX), LIS1 and alpha1-tubulin (TUBA1A), are mutated in these disorders, however corresponding mouse mutants do not show heterotopic neurons in the neocortex. On the other hand, the spontaneously arisen HeCo mouse mutant displays this phenotype. The study of this model reveals novel mechanisms of heterotopia formation. While, HeCo neurons migrate at the same speed as WT, abnormally distributed dividing progenitors were found throughout the cortical wall from E13. Through genetic studies we identified Eml1 as the mutant gene in HeCo mice. No full length transcripts of Eml1 were identified due to a retrotransposon insertion in an intron. Re-expression of Eml1, coding for a microtubule-associated protein, rescues the HeCo progenitor phenotype. We further show that EML1 is mutated in giant ribbon-like heterotopia in human. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

ORGANISM(S): Mus musculus

PROVIDER: GSE56907 | GEO | 2014/05/25

SECONDARY ACCESSION(S): PRJNA244916

REPOSITORIES: GEO

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Project description:Echinoderm microtubule (MT)-associated protein-like 1 (Eml1) is mutated in the HeCo mouse, which exhibits subcortical band heterotopia (SBH), a developmental malformation of the cerebral cortex. EML1 mutations are also found in human patients affected by severe ribbon-like heterotopia, associated with epilepsy and intellectual disability (1). Neural progenitors in the ventricular zone (VZ) of the developing cerebral cortex undergo precisely regulated divisions, and mitotic perturbations contribute to pathological mechanisms (2). Eml1 is expressed in the mouse VZ and ectopic progenitors are present in the mutant developing cortex, when Eml1 is absent, at early stages of development (1). Thus, Eml1 is likely to play a role in neural progenitors during cortical development. We performed cell and molecular biology assays aiming to elucidate the function of Eml1 in neural progenitors, and explored the VZ of the HeCo mutant in order to find morphological perturbations that might explain the initiation of SBH formation (3). As part of this study, we searched for Eml1 molecular partners by pull-downs from mouse cortical extracts at embryonic day E13.5 and mass spectrometry (MS) analyses in order to identify the molecular pathways in which the protein is involved (3). Eml1 is formed by an N-terminal region that contains a dimerization domain and a C-terminal region that forms a ‘tandem atypical propeller in EMLs’ (TAPE) domain. The isolated N-terminal domain strongly binds MTs, while the C-terminal domain preferentially binds tubulin, and its beta-propeller structure is thought also to mediate the interaction with other molecules (4,5). We focused for this study on the N-terminal part of the protein (amino acids 1-178). Future study will validate or elucidate new interactions by using the C-terminal domain and/or the full-length protein. The results obtained from the N terminal MS data, integrated with other experimental findings, allow us to insert Eml1 in a network of proteins that are likely to regulate the assembly and function of the mitotic spindle in neural progenitors (3). More precisely, we showed that the protein regulates MT dynamics and its loss leads to perturbations in metaphase spindle length, which in turn impact progenitor morphology and behavior (3). References 1. Kielar, M., et al. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat. Neurosci. 17, 923–933 (2014). 2. Bizzotto, S., & Francis, F. Morphological and functional aspects of progenitors perturbed in cortical malformations. Front Cell Neurosci. 9, 30; 10.3389/fncel00030 (2015). 3. Bizzotto, S., et al. Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex. 4. Richards, M. W., et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc. Natl. Acad. Sci. U.S.A. 111, 5195–5200 (2014). 5. Richards, M. W., et al. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem. J. 467, 529–536 (2015).

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Mutations in the microtubule-associated protein Eml1 lead to ectopic progenitors and heterotopia formation during cortical development in mouse and human

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