Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells
Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiati...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-06-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122000948 |
| _version_ | 1828404774097125376 |
|---|---|
| author | M.A. Stouffer R. Khalaf-Nazzal C. Cifuentes-Diaz G. Albertini E. Bandet G. Grannec V. Lavilla J.-F. Deleuze R. Olaso M. Nosten-Bertrand F. Francis |
| author_facet | M.A. Stouffer R. Khalaf-Nazzal C. Cifuentes-Diaz G. Albertini E. Bandet G. Grannec V. Lavilla J.-F. Deleuze R. Olaso M. Nosten-Bertrand F. Francis |
| author_sort | M.A. Stouffer |
| collection | DOAJ |
| description | Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior. |
| first_indexed | 2024-12-10T10:42:31Z |
| format | Article |
| id | doaj.art-18ef277b13684ecbb8f8dd28e0de997f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-10T10:42:31Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-18ef277b13684ecbb8f8dd28e0de997f2022-12-22T01:52:16ZengElsevierNeurobiology of Disease1095-953X2022-06-01168105702Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cellsM.A. Stouffer0R. Khalaf-Nazzal1C. Cifuentes-Diaz2G. Albertini3E. Bandet4G. Grannec5V. Lavilla6J.-F. Deleuze7R. Olaso8M. Nosten-Bertrand9F. Francis10INSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, FranceUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, FranceUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, FranceINSERM UMR-S 1270, Paris 75005, France; Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France; Corresponding author at: Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France.Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior.http://www.sciencedirect.com/science/article/pii/S0969996122000948Cortical malformationNeurodevelopmental disorderMouse knockouthippocampusMolecular and cellular analysisMorphology |
| spellingShingle | M.A. Stouffer R. Khalaf-Nazzal C. Cifuentes-Diaz G. Albertini E. Bandet G. Grannec V. Lavilla J.-F. Deleuze R. Olaso M. Nosten-Bertrand F. Francis Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells Neurobiology of Disease Cortical malformation Neurodevelopmental disorder Mouse knockout hippocampus Molecular and cellular analysis Morphology |
| title | Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| title_full | Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| title_fullStr | Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| title_full_unstemmed | Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| title_short | Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| title_sort | doublecortin mutation leads to persistent defects in the golgi apparatus and mitochondria in adult hippocampal pyramidal cells |
| topic | Cortical malformation Neurodevelopmental disorder Mouse knockout hippocampus Molecular and cellular analysis Morphology |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122000948 |
| work_keys_str_mv | AT mastouffer doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT rkhalafnazzal doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT ccifuentesdiaz doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT galbertini doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT ebandet doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT ggrannec doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT vlavilla doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT jfdeleuze doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT rolaso doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT mnostenbertrand doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells AT ffrancis doublecortinmutationleadstopersistentdefectsinthegolgiapparatusandmitochondriainadulthippocampalpyramidalcells |