ABSTRACT
Cajal-Retzius cells (CRs) are peculiar neurons in the developing mammalian cerebral cortex. They robustly secrete Reln, a glycoprotein essential for the establishment of cortical layers through the control of radial migration. We previously identified Gmnc as a crucial fate determinant for P73+ CR subtypes. In Gmnc−/− mutants, P73+ CRs are initially produced and cover the telencephalic vesicle but undergo massive apoptosis resulting in their complete depletion at mid-corticogenesis. Here, we investigated the consequences of such a CR depletion on dorsal cortex lamination and hippocampal morphogenesis. We found that preplate splitting normally occurs in Gmnc−/− mutants but is followed by defective radial migration arrest in the dorsal cortex, an altered cellular organization in the lateral cortex, aberrant hippocampal CA1 folding and lack of vasculature development in the hippocampal fissure. We then performed conditional Reln deletion in P73+ CRs to evaluate its relative contribution and found that only radial migration defects were recapitulated. We concluded that at mid-corticogenesis, CR-derived Reln is required for radial migration arrest and additionally identified Reln-independent functions for CRs in the control of hippocampal fissure formation and CA1 folding.
Footnotes
Author contributions
Conceptualization: V.E., A.P., N.S., F.C.; Data curation: V.E., F.C.; Formal analysis: V.E., B.B., F.C.; Funding acquisition: N.B.-B., A.P., N.S., F.C.; Investigation: V.E., B.B., E.D., Y.S., J.S.M., P.A., M.X.M., F.C.; Methodology: V.E., B.B., Y.S., P.A., M.X.M., A.P., N.S., F.C.; Project administration: F.C.; Resources: R.S., A.P., N.S., F.C.; Software: F.C.; Supervision: A.P., N.S., F.C.; Validation: V.E., B.B., E.D., Y.S., J.S.M., P.A., N.S., F.C.; Visualization: V.E., B.B., F.C.; Writing – original draft: F.C.; Writing – review & editing: V.E., B.B., E.D., Y.S., R.S., A.P., N.S., F.C.
Funding
V.E. was funded by Ecole Doctorale BioSPC and EUR G.E.N.E Graduate School [ANR-17-EURE-0013, funded by Agence Nationale de la Recherche (ANR)]. B.B. was funded by Ecole Doctorale ED3C and ANR-10-LABX-54 MEMO LIFE. J.S.M. was funded by Ecole Doctorale BioSPC. P.A. is a laureate from the Pasteur-Paris University (PPU) International PhD Programme. M.X.M. was funded by École Normale Supérieure and Fondation pour la Recherche Médicale (FRM) (FDT201904008366). This work was supported by IdEx Université Paris Cité (ANR-18-IDEX-0001), State funding from the ANR under the ‘Investissements d'avenir’ program (ANR-10-IAHU-01 and ANR-18-RHUS-005) to the Imagine Institute and NBB. A.P. was funded by grants from ANR (ANR-19-CE16-0017-03) and FRM (Équipe FRM EQU201903007836). N.S. was funded by grants from ANR (ANR-20-CE45-0019, ANR-21-CE16-0016, ANR-22-CE16-0011) and FRM (Équipe FRM EQU202103012767). F.C. was funded by grants from IdEx Université Paris Cité ‘Émergence‘ program (IDEX RM27J21IDXA7_CAJALIDENT) and ANR (ANR-22-CE16-0011-01).
Data and resource availability
Raw and processed data, including a Seurat object corresponding to Fig. 6B, have been deposited in GEO under accession number GSE276037. Comprehensive and annotated R codes used for quality control, analysis and figure layout can be found at https://fcauseret.github.io/P0_GmncKO/.
