Notch and BMP signaling regulate differentiation of rhombic lip-born cerebellar granule cells

Cerebellar granule cells (CGC) are the most abundant neuronsin the mammalian brain and an important system forunraveling molecular and cellular mechanisms underlyingneurogenesis. Math1 is a bHLH transcription factor thatgenetically defines the rhombic lip (RL), which gives rise toCGC and other neurons. To better delineate the effects ofMath1 on differentiation of RL progenitors, we generated andstudied primary cultures of RL cells from Math1::LacZknockout and littermate mouse embryos. RL precursors ofMath1 null mice express CGC-specific markers and maintainMath1 promoter activity both in vivo and in vitro, suggestingthat Math1 is not essential for the initial stages of specificationor survival of CGC. However, Math1 null progenitors do notdownregulate Math1 promoter activity and are unable tooutgrow neurites. Thus, CGC differentiation, but not specifi-cation, depends on Math1, which acts by regulating the level ofmultiple components of the Notch signaling pathway, throughpositive and negative regulatory feedback loops. Bordering theRL is the choroid plexus, a non-neuronal structure, composedof blood vessels enveloped by epithelial cells. We identified astriking decrease in neural differentiation of RL-derived cells,which fail to extend neuritic processes and attenuate Math1promoter activity, when co-cultured with choroid plexus cells.BMP7 and its antagonist NBL1 were identified as novelregulators of differentiation of RL derived, Math1-positive,progenitors. Hence, besides its secretory and barrier functions,the choroid plexus has a novel role in attenuating thedifferentiation of adjacent neural progenitors.