Capicua regulates the survival of Cajal-Retzius cells in the postnatal hippocampus

Programmed cell death is crucial for organ morphogenesis and tissue homeostasis. Understanding programmed cell death in the developing brain is essential for comprehending both normal brain development and neurological disorders. In this study, we utilize Cajal-Retzius (CR) cells, transient neurons that populate the embryonic cortex and are predominantly eliminated in early postnatal stages, as a model to investigate the regulation of programmed cell death. While many CR cells typically undergo postnatal cell death, some persist into adulthood in the hippocampus, influencing local circuits and behaviors. Here, we show that the loss of capicua (CIC), a transcriptional repressor implicated in a rare neurodevelopmental syndrome and multiple cancers, results in aberrant survival of CR cells in the adult hippocampus. Altered cell survival is mediated by the cell-autonomous function of CIC in hippocampal CR cells. Surprisingly, the atypical persistence of CR cells following CIC loss does not impact hippocampal-dependent behaviors or susceptibility to kainic acid-induced seizures. Single-cell transcriptomic analysis unveils previously unrecognized heterogeneity among hippocampal CR cells and suggests a role of CIC in repressing Fgf1 expression. Additionally, we reveal that FGF1 and BCL2 serve as pivotal regulators enhancing CR cell survival in the postnatal hippocampus. Our findings shed light on a previously unacknowledged role of CIC upstream of FGF signaling and elucidate the apoptosis mechanism governing developmental programmed CR cell death. Overall design: Four ?Np73-Cre; Cicflox/+; tdT and four ?Np73-Cre; Cicflox/flox; tdT mice (littermates) at P14 were perfused with artificial cerebrospinal fluid (aCSF; 87 mM NaCl; 2.5 mM KCl; 1.25 mM NaH2PO4; 26 mM NaHCO3; 75 mM sucrose; 20 mM glucose; 2 mM CaCl2; 2 mM MgSO4) equilibrated in carbogen (95% O2, 5% CO2) via a gas stone. The brain was promptly removed and kept in aCSF as the hippocampus was dissected. Dissected tissue was kept submerged in aCSF saturated with carbogen on ice.