FoxP1 marks medium spiny neurons from precursors to maturity and is required for their differentiation

Abstract

Identifying the steps involved in striatal development is important both for understanding the striatum in health and disease, and for generating protocols to differentiate striatal neurons for regenerative medicine. The most prominent neuronal subtype in the adult striatum is the medium spiny projection neuron (MSN), which constitutes more than 85% of all striatal neurons and classically expresses DARPP-32. Through a microarray study of genes expressed in the whole ganglionic eminence (WGE: the developing striatum) in the mouse, we identified the gene encoding the transcription factor Forkhead box protein P1 (FoxP1) as the most highly up-regulated gene, thus providing unbiased evidence for the association of FoxP1 with MSN development. We also describe the expression of FoxP1 in the human fetal brain over equivalent gestational stages. FoxP1 expression persisted through into adulthood in the mouse brain, where it co-localised with all striatal DARPP-32 positive projection neurons and a small population of DARPP-32 negative cells. There was no co-localisation of FoxP1 with any interneuron markers. FoxP1 was detectable in primary fetal striatal cells following dissection, culture, and transplantation into the adult lesioned striatum, demonstrating its utility as an MSN marker for transplantation studies. Furthermore, DARPP-32 expression was absent from FoxP1 knock-out mouse WGE differentiated in vitro, suggesting that FoxP1 is important for the development of DARPP-32-positive MSNs. In summary, we show that FoxP1 labels MSN precursors prior to the expression of DARPP-32 during normal development, and in addition suggest that FoxP1 labels a sub-population of MSNs that are not co-labelled by DARPP-32. We demonstrate the utility of FoxP1 to label MSNs in vitro and following neural transplantation, and show that FoxP1 is required for DARPP-32 positive MSN differentiation in vitro.

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

“…Analyzing FOXP1 (variants associated with obesity could disturb the binding site of this TF) has been previously associated with speech development, and deleterious genetic variants are known to cause FOXP1 syndrome (Siper et al., ); patients with this syndrome have psychiatric alterations and almost 30% of them are obese (Le Fevre et al., ; Lloveras et al., ), suggesting a possible link between FOXP1 and obesity. FOXP1 is a TF critical in the fate of adult striatum medium spiny neurons projection and its transcript is highly up‐regulated in the whole ganglionic eminence (Precious et al., ). A possible link between striatum and obesity has been found in a neuroimaging study using positron emission tomography, and reported that the striatum was the most altered in diet‐induced obesity, which reinforces a possible link between the brain and obesity (Michaelides et al., ).…”

“…TA B L E 3 Report of variants that disrupted a transcription factor binding site (Precious et al, 2016). A possible link between striatum and obesity has been found in a neuroimaging study using positron emission tomography, and reported that the striatum was the most altered in diet-induced obesity, which reinforces a possible link between the brain and obesity (Michaelides et al, 2018).…”

Single-cell analysis of Foxp1-driven mechanisms essential for striatal development

“…Previous in vitro work found that loss of Foxp1 reduced the expression of DARPP-32 (Ppp1r1b), a critical phosphatase in the dopamine signaling cascade 33 . We show this decrease in DARPP-32 is specific to iSPNs in vivo ( Supplementary Fig.…”

“…Expression of Foxp1 begins in the LGE at E12.5 with enrichment in the marginal zone and is maintained throughout striatal development 26,32 . While previous studies have suggested a role for Foxp1 in striatal development 33,34,35 , no study has examined the contribution of Foxp1 to striatal circuit organization in a cell-specific manner.…”

Transplantation in HD: Are We Transplanting the Right Cells?

“…Thus, when developing protocols for the generation of such cells, particularly from PSC sources, it is vital to have other markers available in order to determine that the differentiation progression is appropriate to the desired lineage and phenotype. Two such candidate markers, FoxP1 and CTIP2, have been identified as important markers, both of which label MSN precursor cells and colabel with mature DARPP-32 immunopositive MSNs [65,66].…”