Mouse cortical organoids reveal key functions of p73 isoforms: TAp73 governs the establishment of the archetypical ventricular-like zones while DNp73 is central in the regulation of neural cell fate.

INTRODUCTION

Neurogenesis is tightly regulated in space and time, ensuring the correct development and organization of the central nervous system. Critical regulators of brain development and morphogenesis in mice include two members of the p53 family: p53 and p73. However, dissecting the functions of these factors and their various isoforms in brain development is challenging due to their pleiotropic effects. Understanding their role, particularly in neurogenesis and brain morphogenesis, requires innovative experimental approaches.

METHODS

To address these challenges, we developed an efficient and highly reproducible protocol to generate mouse brain organoids from pluripotent stem cells. These organoids contain neural progenitors and neurons that self-organize into rosette-like structures resembling the ventricular zone of the embryonic forebrain. Using this model, we generated organoids from p73-deficient mouse cells to investigate the roles of p73 and its isoforms (TA and DNp73) during brain development.

RESULTS AND DISCUSSION

Organoids derived from p73-deficient cells exhibited increased neuronal apoptosis and reduced neural progenitor proliferation, linked to compensatory activation of p53. This closely mirrors previous observations, confirming that p73 plays a pivotal role in brain development. Further dissection of p73 isoforms function revealed a dual role of p73 in regulating brain morphogenesis, whereby TAp73 controls transcriptional programs essential for the establishment of the neurogenic niche structure, while DNp73 is responsible for the precise and timely regulation of neural cell fate. These findings highlight the distinct roles of p73 isoforms in maintaining the balance of neural progenitor cell biology, providing a new understanding of how p73 regulates brain morphogenesis.