Presenilin-dependent ErbB4 Nuclear Signaling Regulates Astrogenesis via PARP1

Abstract

Precise timing of astrogenesis during brain development is essential for proper neural circuit assembly, yet the molecular mechanisms governing this process remain incompletely understood. Here, we identify a novel nuclear signaling pathway initiated by the presenilin-dependent proteolytic release of the ErbB4 receptor intracellular domain (E4ICD) that regulates astrocyte differentiation via direct interaction with Poly(ADP-ribose) Polymerase 1 (PARP1). Upon ligand stimulation, E4ICD forms a complex with PARP1, inducing PARP1 tyrosine phosphorylation and enzymatic activation. This complex translocates to the nucleus, where it binds to the GFAP promoter, repressing its transcription. Loss of ErbB4 or PARP1 abolishes these effects, leading to increased differentiation of neural precursor cells into astrocytes in vitro, and elevated astrocytic gene expression in the neonatal brain in vivo. Notably, the E4ICD binding sites in the GFAP promoter overlap with those of Notch signaling, suggesting that these signaling pathways have antagonistic transcriptional roles in the control of glial fate. These findings establish a previously unappreciated RTK-PARP1 nuclear signaling axis that integrates extracellular cues to regulate neurodevelopmental lineage decisions, expanding the known functional repertoire of PARP1 beyond DNA damage and stress responses.