ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period.

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we report that fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces bone morphogenic protein 7 (Bmp7) expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and Sonic Hedgehog (SHH) signaling mutually inhibit each other in cortical RG cells. We provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We propose that the expansion of the mammalian cortex, notably in human, is driven by the ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the relatively short cortical neurogenic period in mice is partly due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.

Context-dependent regulation of Notch signaling in glial development and tumorigenesis.

In the mammalian brain, Notch signaling maintains the cortical stem cell pool and regulates the glial cell fate choice and differentiation. However, the function of Notch in regulating glial development and its involvement in tumorigenesis have not been well understood. Here, we show that Notch inactivation by genetic deletion of Rbpj in stem cells decreases astrocytes but increases oligodendrocytes with altered internal states. Inhibiting Notch in glial progenitors does not affect cell generation but instead accelerates the growth of Notch-deprived oligodendrocyte progenitor cells (OPCs) and OPC-related glioma. We also identified a cross-talk between oligodendrocytes and astrocytes, with premyelinating oligodendrocytes secreting BMP4, which is repressed by Notch, to up-regulate GFAP expression in adjacent astrocytes. Moreover, Notch inactivation in stem cells causes a glioma subtype shift from astroglia-associated to OPC-correlated patterns and vice versa. Our study reveals Notch's context-dependent function, promoting astrocytes and astroglia-associated glioma in stem cells and repressing OPCs and related glioma in glial progenitors.

The transcription factor Zfp503 promotes the D1 MSN identity and represses the D2 MSN identity.

The striatum is primarily composed of two types of medium spiny neurons (MSNs) expressing either D1- or D2-type dopamine receptors. However, the fate determination of these two types of neurons is not fully understood. Here, we found that D1 MSNs undergo fate switching to D2 MSNs in the absence of Zfp503. Furthermore, scRNA-seq revealed that the transcription factor Zfp503 affects the differentiation of these progenitor cells in the lateral ganglionic eminence (LGE). More importantly, we found that the transcription factors Sp8/9, which are required for the differentiation of D2 MSNs, are repressed by Zfp503. Finally, sustained Zfp503 expression in LGE progenitor cells promoted the D1 MSN identity and repressed the D2 MSN identity. Overall, our findings indicated that Zfp503 promotes the D1 MSN identity and represses the D2 MSN identity by regulating Sp8/9 expression during striatal MSN development.

Dlx1/2-dependent expression of Meis2 promotes neuronal fate determination in the mammalian striatum.

The striatum is a central regulator of behavior and motor function through the actions of D1 and D2 medium-sized spiny neurons (MSNs), which arise from a common lateral ganglionic eminence (LGE) progenitor. The molecular mechanisms of cell fate specification of these two neuronal subtypes are incompletely understood. Here, we found that deletion of murine Meis2, which is highly expressed in the LGE and derivatives, led to a large reduction in striatal MSNs due to a block in their differentiation. Meis2 directly binds to the Zfp503 and Six3 promoters and is required for their expression and specification of D1 and D2 MSNs, respectively. Finally, Meis2 expression is regulated by Dlx1/2 at least partially through the enhancer hs599 in the LGE subventricular zone. Overall, our findings define a pathway in the LGE whereby Dlx1/2 drives expression of Meis2, which subsequently promotes the fate determination of striatal D1 and D2 MSNs via Zfp503 and Six3.

Transcription factors Bcl11a and Bcl11b are required for the production and differentiation of cortical projection neurons.

The generation and differentiation of cortical projection neurons are extensively regulated by interactive programs of transcriptional factors. Here, we report the cooperative functions of transcription factors Bcl11a and Bcl11b in regulating the development of cortical projection neurons. Among the cells derived from the cortical neural stem cells, Bcl11a is expressed in the progenitors and the projection neurons, while Bcl11b expression is restricted to the projection neurons. Using conditional knockout mice, we show that deficiency of Bcl11a leads to reduced proliferation and precocious differentiation of cortical progenitor cells, which is exacerbated when Bcl11b is simultaneously deleted. Besides defective neuronal production, the differentiation of cortical projection neurons is blocked in the absence of both Bcl11a and Bcl11b: Expression of both pan-cortical and subtype-specific genes is reduced or absent; axonal projections to the thalamus, hindbrain, spinal cord, and contralateral cortical hemisphere are reduced or absent. Furthermore, neurogenesis-to-gliogenesis switch is accelerated in the Bcl11a-CKO and Bcl11a/b-DCKO mice. Bcl11a likely regulates neurogenesis through repressing the Nr2f1 expression. These results demonstrate that Bcl11a and Bcl11b jointly play critical roles in the generation and differentiation of cortical projection neurons and in controlling the timing of neurogenesis-to-gliogenesis switch.