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 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 SVZ. 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.

https://journals.biologists.com/dev/article-pdf/149/4/dev200035/2132541/dev200035.pdf

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

ABSTRACT Fibroblast growth factor 8 (FGF8), acting through the fibroblast growth factor receptor 1 (FGFR1), has an important role in the development of gonadotropin-releasing hormone-expressing neurons (GnRH neurons). We hypothesized that FGF8 regulates differentiation of human GnRH neurons in a time- and dose-dependent manner via FGFR1. To investigate this further, human pluripotent stem cells were differentiated during 10 days of dual-SMAD inhibition into neural progenitor cells, followed either by treatment with FGF8 at different concentrations (25 ng/ml, 50 ng/ml or 100 ng/ml) for 10 days or by treatment with 100 ng/ml FGF8 for different durations (2, 4, 6 or 10 days); cells were then matured through DAPT-induced inhibition of Notch signaling for 5 days into GnRH neurons. FGF8 induced expression of GNRH1 in a dose-dependent fashion and the duration of FGF8 exposure correlated positively with gene expression of GNRH1 (P<0.05, Rs=0.49). However, cells treated with 100 ng/ml FGF8 for 2 days induced the expression of genes, such as FOXG1, ETV5 and SPRY2, and continued FGF8 treatment induced the dynamic expression of several other genes. Moreover, during exposure to FGF8, FGFR1 localized to the cell surface and its specific inhibition with the FGFR1 inhibitor PD166866 reduced expression of GNRH1 (P<0.05). In neurons, FGFR1 also localized to the nucleus. Our results suggest that dose- and time-dependent FGF8 signaling via FGFR1 is indispensable for human GnRH neuron ontogeny. This article has an associated First Person interview with the first author of the paper.

https://journals.biologists.com/dmm/article-pdf/15/8/dmm049436/2157742/dmm049436.pdf

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

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.

/pdf/the-transcription-factor-zfp503-promotes-the-d1-msn-identity-1wyyru5r.pdf

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

Fibroblast growth factor 8 (FGF8), acting through the fibroblast growth factor receptor 1 (FGFR1), has an important role in the development of GnRH neurons. We hypothesized that FGF8 regulates human GnRH neuron differentiation in a time- and dose-dependent manner via FGFR1. Human pluripotent stem cells were differentiated to GnRH neurons with ten days of dual-SMAD inhibition, followed by FGF8 (25 ng/ml, 50 ng/ml or 100 ng/ml for ten days; or 100 ng/ml for two, four, six, and ten days), and Notch inhibition for five days. FGF8 induced expression of GNRH1 in a dose-dependent fashion and the duration of FGF8 exposure correlated positively with GNRH1 expression (P<0.05, Rs=0.49). However, two days of FGF8 (100 ng/ml) induced expression of its target genes such as FOXG1, ETV5, and SPRY2, and continued FGF8 induced dynamic expression of several genes. During FGF8 exposure, FGFR1 localized to the cell surface, and its specific inhibition with PD166866 reduced GNRH1 expression (P<0.05). In neurons, FGFR1 also localized to the nucleus. Our results suggest that dose- and time-dependent FGF8 signaling via FGFR1 is indispensable for human GnRH neuron ontogeny.

Time and dose-dependent effects of FGF8-FGFR1 signaling in GnRH neurons derived from human pluripotent stem cells.

Abstract The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 -positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSN identity and repressing D1-MSN identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2-like MSNs survived normally in adulthood. Taken together, our findings supported that Sp9 was sufficient to promote D2-MSN identity and repress D1-MSN identity, and Sp9 was a negative regulator of D1-MSN fate. 

/pdf/transcription-factor-sp9-is-a-negative-regulator-of-d1-type-23plhpg2.pdf

Transcription factor Sp9 is a negative regulator of D1-type MSN development

Specification of the progenitors' regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factor Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE expands ventrally, and the vLGE, MGE, and septum get smaller. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.

/pdf/transcription-factor-vax1-regulates-the-regional-10oc6ui0mw.pdf

Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium Through Repressing Gsx2

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Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium Through Repressing Gsx2