Jaime Fabra-Beser

Neural stem cells (NSCs) sustain neurogenesis within specialized niches, yet how adhesion-dependent mechanisms during development control lifelong behavior remains unclear. Here, we identify Afadin, a core adherens junction protein, as a regulator. Dorsal loss of Afadin during development drives formation of a stable, ventricular-independent ectopic germinal zone in the neocortex, populated by self-renewing, multipotent NSCs sustaining neurogenesis into adulthood. This ectopic niche emerges within a disorganized cortical environment reminiscent of subcortical band heterotopia, a malformation linked to human neurodevelopmental disorders. Concomitantly, the canonical ventricular-subventricular zone (V-SVZ) is disrupted, with persistent NSC activation, altered ependymal specification, ventricular disorganization, and increased neurogenesis. Transcriptomic profiling of the V-SVZ reveals a shift from adhesion- and quiescence-associated programs toward proliferative and neurogenic states through cell-autonomous and non-cell-autonomous mechanisms. Mosaic postnatal or adult deletion confirms a cell-intrinsic role of Afadin in NSC activation. Together, these findings reveal flexibility and plasticity of NSCs across the lifespan.

Stem cells are generally thought to depend on specialized niches that provide signals for their long-term maintenance. Whether stem-cell competence is intrinsically constrained by anatomical organization remains unclear. Here, we show that neural stem cells can establish and sustain functional persistent stem-cell populations outside their normal anatomical context. Using developmental deletion of the cell-adhesion regulator Afadin as a tool to disrupt cortical tissue organization, we find that neural progenitors are displaced from the ventricular surface and establish an ectopic germinal zone (EGZ) into advanced adulthood. EGZ stem-cell populations retain self-renewal and multilineage differentiation capacity throughout this period. In parallel, the ventricular-subventricular zone (V-SVZ) undergoes persistent reorganization of tissue architecture, cellular composition, molecular state, and stem-cell activity. Together, these findings reveal unexpected plasticity in the relationship between stem cells and their tissue environment, suggesting that canonical niche anatomy may constrain where stem cells normally reside without defining the limits of functional stem-cell competence.

Mosaic mutations in the X-linked cell adhesion molecule Protocadherin 19 (PCDH19) lead to epilepsy with cognitive impairment, whereas complete absence of functional protein, although possibly linked to autistic features, does not elicit any seizures. It is believed that mosaic expression of PCDH19 leads to defective neuronal communication, but whether further roles beyond cell adhesion are critical for PCDH19 function in the cortex is currently unknown. We confirm that the proteolytic processing of PCDH19, previously described in hippocampal neurons, also takes place in mouse cortical neurons in vivo and show that nuclear transport of its intracellular domain is mediated by importins. RNAseq analysis further indicates that the intracellular domain of PCDH19 leads to broad transcriptomic changes. Finally, we use in utero electroporation to provide the first in vivo data about the role of this cleaved intracellular domain in upper layer cortical neurons of male and female mice, where it reduces spine density through an increase in Xlr gene expression without affecting overall dendritic morphology. Our results suggest that PCDH19 could act as an activity sensor in a synapse to nucleus signalling pathway involved in synaptic homeostasis. Significance statement We investigate non-adhesive functions of the epilepsy-linked cell adhesion protein PCDH19 and uncover a signalling role for its intracellular domain in cortical neurons. Beyond its established function in cell adhesion, we show that proteolytic cleavage of PCDH19 and nuclear import of its intracellular fragment leads to transcriptomic changes that impact dendritic spine density through the upregulation of Xlr genes. These findings suggest that PCDH19 may act as a synaptic activity sensor, linking membrane dynamics to nuclear responses in the regulation of synaptic homeostasis.

Neural stem cells (NSCs) in the adult murine subependymal zone balance their self-renewal capacity and glial identity with the potential to generate neurons during the lifetime. Adult NSCs exhibit lineage priming via pro-neurogenic fate determinants. However, the protein levels of the neural fate determinants are not sufficient to drive direct differentiation of adult NSCs, which raises the question of how cells along the neurogenic lineage avoid different conflicting fate choices, such as self-renewal and differentiation. Here, we identify RNA-binding protein MEX3A as a post-transcriptional regulator of a set of stemness associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A regulates a quiescence-related RNA signature in activated NSCs that is needed for their return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A is a pivotal regulator of adult murine neurogenesis acting as a translational remodeller.

The neocortex is an exquisitely organized structure achieved through complex cellular processes from the generation of neural cells to their integration into cortical circuits after complex migration processes. During this long journey, neural cells need to establish and release adhesive interactions through cell surface receptors known as cell adhesion molecules (CAMs). Several types of CAMs have been described regulating different aspects of neurodevelopment. Whereas some of them mediate interactions with the extracellular matrix, others allow contact with additional cells. In this review, we will focus on the role of two important families of cell–cell adhesion molecules (C-CAMs), classical cadherins and nectins, as well as in their effectors, in the control of fundamental processes related with corticogenesis, with special attention in the cooperative actions among the two families of C-CAMs.

The neocortex is an exquisitely organized structure achieved through complex cellular processes from the generation of neural cells to their integration into cortical circuits after complex migration processes. During this long journey, neural cells need to stablish and release adhesive interactions through cell surface receptors known as cell adhesion molecules (CAMs). Several types of CAMs have been described regulating different aspects of neurodevelopment. Whereas some of them mediate interactions with the extracellular matrix, others allow contacts with additional cells. In this review, we will focus on the role of two important families of cell-cell adhesion molecules (C-CAMs), classical cadherins and nectins, as well as in their effectors, in the control of fundamental processes related with corticogenesis, with especial attention in the cooperative actions among the two families of C-CAMs.