A role for Retinoblastoma 1 in hindbrain morphogenesis by regulating GBX family

The hindbrain, which develops from the anterior end of the neural tube expansion, can differentiate into the metencephalon and myelencephalon, with varying sizes and functions. The midbrain–hindbrain boundary (MHB) and hindbrain myelencephalon/ventral midline (HMVM) are known to be the source of the progenitors for the anterior hindbrain and myelencephalon, respectively. However, the molecular networks regulating hindbrain morphogenesis in these structures remain unclear. In this study, we show that retinoblastoma 1 (rb1) is highly expressed at the MHB and HMVM in zebrafish. Knocking out rb1in mice and zebrafish results in an enlarged hindbrain due to hindbrain neuronal hyperproliferation. Further study reveals that Rb1 controls the hindbrain morphogenesis by suppressing the expression of Gbx1/Gbx2, essential transcription factors for hindbrain development, through its binding to E2f3/Hdac1, respectively. Interestingly, we find that Gbx1 and Gbx2 are expressed in different types of hindbrain neurons, suggesting distinct roles in hindbrain morphogenesis. In summary, our study clarifies the specific role of RB1 in hindbrain neural cell proliferation and morphogenesis by regulating the E2f3–Gbx1 axis and the Hdac1–Gbx2 axis. These findings provide a research paradigm for exploring the differential proliferation of neurons in various brain regions.