title: 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.
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: S V
authors.initials: SV
authors.lastname: Precious
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: C M
authors.initials: CM
authors.lastname: Kelly
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: A E
authors.initials: AE
authors.lastname: Reddington
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: N N
authors.initials: NN
authors.lastname: Vinh
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: R C
authors.initials: RC
authors.lastname: Stickland
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom; Central European Institute of Technology (CEITEC), Institute of Anatomy, Masaryk University, A1/064, Kamenice 3, 625 00 Brno, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Pekarik
authors.affiliation: Department of Obstetrics and Gynaecology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Scherf
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Jeyasingham
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Glasbey
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Holeiter
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.affiliation: Molecular Biosciences Research Division, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
authors.forename: M V
authors.initials: MV
authors.lastname: Taylor
authors.affiliation: Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom. Electronic address: rosserae@cf.ac.uk.
authors.forename: A E
authors.initials: AE
authors.lastname: Rosser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004622:Embryo, Mammalian; D004706:Endodeoxyribonucleases; D005333:Fetus / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D002352:Carrier Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human
keywords: DARPP-32; FoxP1; Huntington's disease; Medium spiny neurons; Neural transplantation