Details

Autor(en) / Beteiligte

• Kielar, Michel
• Tuy, Françoise Phan Dinh
• Bizzotto, Sara
• Lebrand, Cécile
• de Juan Romero, Camino
• Poirier, Karine
• Oegema, Renske
• Mancini, Grazia Maria
• Bahi-Buisson, Nadia
• Olaso, Robert
• Le Moing, Anne-Gaëlle
• Boutourlinsky, Katia
• Boucher, Dominique
• Carpentier, Wassila
• Berquin, Patrick
• Deleuze, Jean-François
• Belvindrah, Richard
• Borrell, Victor
• Welker, Egbert
• Chelly, Jamel
• Croquelois, Alexandre
• Francis, Fiona

Titel

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Ist Teil von

• Nature neuroscience, 2014-07, Vol.17 (7), p.923-933

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2014

Quelle

Psychology & Behavioral Sciences Collection

Beschreibungen/Notizen

• Kielar and colleagues identified mutations in the microtubule-associated protein Eml1 in patients with severe cortical heterotopia. Using animal and cell models, the authors found that Eml1 inactivation alters spindle orientation in dividing neuronal progenitors during early corticogenesis, leading to their detachment from the ventricular zone, their accumulation in the intermediate zone and the subsequent development of subcortical heterotopia. Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX , PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1 , encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.