Cortical Development & Microcephaly

How the human brain develops from the embryonic stages to adulthood, and how it reaches its final size and organisation, are at the heart of our scientific questions. Our group is interested in cortical development and, in particular, developmental abnormalities that lead to human microcephaly, a relatively common neurodevelopmental disorder that manifests as congenital (primary microcephaly) or postnatal (secondary microcephaly) brain development deficits and can result from genetic variants or environmental causes during pregnancy. To model these pathologies and dissect the cellular and molecular mechanisms involved, we are developing cortical organoids from induced pluripotent stem cells (hiPSCs) derived from the cells of patients with microcephaly.

We have identified centrosome defects during corticogenesis and Golgi transport abnormalities as recurrent causes of microcephaly, and our group has contributed significantly to the identification of several microcephaly genes associated with centrosome abnormalities (Passemard, Neurology 2009; Nicholas, Nat Genet 2010; Harding, Am J Hum Genet 2016; Létard, Hum Mutat 2018) or the Golgi apparatus (Dimitrov, Hum Mol Genet 2009; Dupuis, Hum Mutat 2013; Izumi, Am J Hum Genet 2016; Uwineza, Eur J Med Genet 2019). The products of genes involved in centrosomopathies clearly play a role in cell cycle regulation and mitotic spindle dynamics during neural progenitor cell division, while those of Golgipathy genes appear to be important for pre- or post-Golgi vesicle trafficking. This suggests that very different pathomechanisms can lead to microcephaly. Recently, abnormalities in mitochondrial metabolism have also been characterised in certain microcephalies.
Our group is interested in
i. the phenotypic and molecular characterisation of new centrosomopathies and Golgipathies
ii. understanding the pathophysiological roles of the centrosome, Golgi apparatus and mitochondria in the development of microcephaly

Our experimental approaches include brain imaging and modelling of brain development using organoids derived from human induced pluripotent stem cells (hiPSCs) from patients and mouse models with genes of interest knocked out.

Permanent Members

Albert Alexandra, Assistant-Engineer (Inserm)

Drunat Séverine, PH (Hospital)

El Ghouzzi Vincent, Research Director (CNRS)

Jacquier Sandrine, Assistant-Engineer (Inserm)

Lebon Sophie, Research Engineer (Inserm)

Le Guilloux Gwendoline, Assistant-Engineer (Inserm)

Lévy Jonathan, PH (Hospital)

Masson Justine, Researcher (CRHC CNRS)

Moussay Manon, Research Engineer (Inserm)

Papp Bela, Researcher (CRCN Inserm)

Passemard Sandrine, PUPH, Child Neurologist (Hospital)

Rak Malgorzata, Researcher (CRCN CNRS)

Verloes Alain, PUPH (Hospital)

Vial Yoann, MCUPH (Hospital)

Publications

1. Albert A., Couture L., Piumi F., Lebon S., Gressens P., Coulpier M., Amara A., El Ghouzzi V*., Meertens L*. Oropouche virus infects human neural progenitor cells and alters the growth of brain organoids. BioRxiv 2025
2. Lebon S., Bruneel A., Drunat S., Albert A., Csaba Z., Elmaleh M., Ntorkou A., Ténier Y., Fenaille F., Gressens P., Passemard S., Boespflug-Tanguy O., Dorboz I., El Ghouzzi V. A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects. Life Sci. Alliance, 2025 Feb 11;8(4)
3. Gins C., Guimiot F., Drunat S., Prévost C., Rosenblatt J., Capri Y., Letard P., Khung-Savatovsky S., Mahi Henni M.A., Chafai Elalaoui S., Alison M., Guilmin Crepon S., Gressens P., Verloes A., Basto R., El Ghouzzi V., Passemard S. Radial microbrain (micrencephaly) is caused by a recurrent variant in the RTTN gene. Neurol. Genet., 2025, 11, e200221.
4. Nava C., Cogne B., Santini A., Leitão E., Lecoquierre F., Chen Y., Stenton S.L., Besnard T., Heide S., Baer S., Jakhar A., …, Delahaye-Duriez A…..Passemard S….Depienne C. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption Nat. Genet., 2025 Jun;57(6):1374-1388.
5. Pedraza M., Grampa V., Scotto-Lomassese S., Puech J., Muzerelle A., Mohammad A., Lebon S., Renier N., Métin C., Masson J. The ciliary kinesin KIF7 controls the development of the cerebral cortex by acting differentially on SHH-signaling in dorsal and ventral forebrain. eLife, 2025, 13, RP100328.
6. Gerasimenko A., Mignot C., Naggara O., Coulet F., Ekram S., Heide S., Sorato C., Mazowiecki M., Perrin L., Colas C., Cusin V., Caux F., Dardenne A., El Chehadeh S., Verloes A., Maurey H., Afenjar A., Petit F., Barete S., Boespflug-Tanguy O., Bourrat E., Capri Y., Ciorna V., Deb W., Doummar D., Perrier A., Guédon A., Houdart E., Isidor B., Jacquemont M.L., Buffet C., Mercier S., Passemard S., Riquet A., Ruaud L., Schaefer E., Heron D., Bisdorff A., Benusiglio P.R. Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome Clin. Genet. 2024 Jul;106(1):90-94.
7. Frost F.G., Morimoto M., Sharma P., Ruaud L., Belnap N., Calame D.G., Uchiyama Y., Matsumoto N., Oud M.M., Ferreira E.A., Narayanan V., Rangasamy S., Huentelman M., Emrick L.T., Sato-Shirai I., Kumada S., Wolf N.I., Steinbach P.J., Huang Y. Pusey B.N., Passemard S., Levy., Drunat S., Vincent M., Guet A., Agolini E., Novelli A., Digilio M.C., Rosenfeld J.A., Murphy J.L., Lupski J.R., Vezina G., Macnamara E.F., Adams D.R., Acosta M.T., Tifft C.J., Gahl W.A., Malicdan M.C.V.  Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis. Am J Hum Genet. 2023 Apr 6;110(4):663-680. 
8. El Ghouzzi V., Boncompain G. Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development Nat. Commun., 2022, 13, 7397.
9. Farcy S., Albert A., Gressens P., Baffet A.*, El Ghouzzi V*. Cortical Organoids to Model Microcephaly. Cells,  2022 , 11, 2135.
10. Ruaud L., Drunat S., Elmaleh-Berges M., Ernault A., Crepon SG., El Ghouzzi V., Auvin S., Verloes A., El Ghouzzi V. Neurological outcome in WDR62 primary microcephaly. Dev. Med Child Neurol., 2022, 64, 509-517.
11. Masson J., El Ghouzzi V. Golgi dysfunctions in ciliopathies Cells, 2022, 11, 2773.
12. Nasser H., Vera L., Elmaleh-Bergès M., Steindl K., Létard P., Teissier N., Ernault A., Guimiot F., Afenjar A., Moutard M.L., Héron D., Alembik Y., Montchilova M., Milani P., Rigaudière F., Kubis N., Pouvreau N., Gressens P., Verloes A., Rauch A., El Ghouzzi V., Drunat S., Passemard S. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects. J. Med. Genet. 2020, 57, 389-399
13. Passemard S., Perez F., Gressens P., El Ghouzzi V. Endoplasmic reticulum and Golgi stress in microcephaly. Cell Stress, 2019, 3, 369-384.
14. Uwineza A., Caberg J.H., Hitayezu J., Wenric S., Mutesa L., Vial Y., Drunat S., Passemard S., Verloes A., El Ghouzzi V., Bours V. VPS51 biallelic variants cause microcephaly with brain malformations. Eur. J. Med. Genet., 2019, 62, 103704-708.
15. Rasika S., Passemard S., Verloes A., Gressens P., El Ghouzzi V. Golgipathies in neurodevelopment : A new view of old defects. Dev. Neurosci., 2018, 40, 396-416.
16. Létard P., Drunat S., Vial Y., Duerinckx S., Ernault A., Amram D., Arpin S., Bertoli M., Busa T., Ceulemans B., Desir J., Doco-Fenzy M., Chafai Elalaoui S., Devriendt K., Faivre L., Francannet C., Geneviève D., Gérard M., Gitiaux C., Julia S., Lebon S., Lubala T., Mathieu-Dramard M., Maurey H., Metreau J., Nasserereddine S., Nizon M., Pierquin G., Pouvreau N., Rivier-Ringenbach C., Rossi M., Schaefer E., Sefiani A., Sigaudy S., Sznajer Y., Tunca Y., Guilmin Crepon S., Alberti C., Elmaleh-Bergès M., Benzacken B., Wollnick B., Woods G, Rauch A., Abramowicz A., El Ghouzzi V., Gressens P., Verloes A., Passemard S. Autosomal recessive primary microcephaly due to ASPM mutations: an update. Hum. Mutat., 2018, 39, 319-332.
17. Patwardhan D., Mani S., Passemard S., Gressens P., El Ghouzzi V. STIL balancing microcephaly and cancer. Cell Death Dis., 2018, 9, 65-76.
18. Passemard S., Perez F., Colin-Lemesre E., Rasika S., Gressens P., El Ghouzzi V. Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”. Prog. Neurobiol., 2017, 153, 46-63.
19. Cavallin M., Rujano M.A., Bednarek N., Medina-Cano D., Bernabe Gelot A., Drunat S., Maillard C., Garfa-Traore M., Bole C., Nitschké P., Beneteau C., Besnard T., Cogné B., Eveillard M., Kuster A., Poirier K., Verloes A., Martinovic J., Bidat L., Rio M., Lyonnet S., Reilly M.L., Boddaert N., Jenneson-Liver M., Motte J., Doco-Fenzy M., Chelly J., Attie-Bitach T., Simons M., Cantagrel V., Passemard S., Baffet A., Thomas S., Bahi-Buisson N. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. Brain, 2017, 140, 2597-2609.
20. Passemard S., Verloes A., Billette de Villemeur T., Boespflug O., Hernandez K., Laurent M., Isidor B., Alberti C., Pouvreau N., Drunat S., Gérard B., El Ghouzzi V., Gallego J., Elmaleh-Bergès M., Huttner W.B., Eliez S., Gressens P., Schaer M. Abnormal spindle-like microcephaly (ASPM) mutations strongly disrupt neocortex but spare hippocampus and long-term memory. Cortex, 2016, 74, 158-176.
21. Izumi K., Brett M., Nishi E., Drunat S., Tan E., Fujiki K., Lebon S., Cham B., Masuda K., Arakawa M., Jacquinet A., Yamazumi Y., Chen S., Verloes A., Okada Y., Nakamura T., Akiyama T., Gressens P., Foo R., Passemard S., Tan E., El Ghouzzi V.*, Shirahige K*. ARCN1 mutations cause a recognizable craniofacial syndrome due to COPI-mediated transport defects. Am. J. Hum. Genet., 2016, 99, 451-459.
22. Harding B.N., Moccia A., Soukarieh O., Tubeuf H., Drunat S., Chitty L.S., Verloes A., Gressens P., El Ghouzzi V., Joriot S., Passemard S., Di Cunto F., Martins A., Bielas S.L. Mutations in Citron Kinase cause recessive microlissencephaly with multinucleated neurons.  Am. J. Hum. Genet., 2016, 99, 511-520.
23. El Ghouzzi V., Bianchi F.T., Molineris I., Mounce B.C., Berto G.E., Rak M., Lebon S., Aubry L., Tocco C., Gai M., Chiotto A.M.A., Sgrò, Pallavicini G., Simon-Loriere E., Passemard S., Vignuzzi M., Gressens P., Di Cunto F. ZIKA Virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly. Cell Death Dis., 2016, 7, e2440.
24. Dupuis N., Fafouri A., Bayot A., Kumar K., Lecharpentier T., Ball G., Edwards A.D., Bernard V., Dournaud P., Drunat S., Vermelle-Andrzejewski M., Vilain C., Abramowicz M., Désir J., Bonaventure J., Gareil N., Boncompain G., Csaba Z., Perez F., Passemard S., Gressens P., El Ghouzzi V. Dymeclin deficiency causes postnatal microcephaly, hypomyelination and reticulum-to-Golgi trafficking defects in mice and humans. Hum. Mol. Genet., 2015, 24, 2771-2783.
25. Srivastava R., Kumar M., Peineau S., Csaba Z., Mani S., Gressens P.,El Ghouzzi V. Conditional induction of Math1 specifies embryonic stem cells to cerebellar granule neuron lineage and promotes differentiation into mature granule neurons. Stem Cells, 2013, 31, 652-665.