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.

Brain Repair Group Sir Martin Evans Building School of Biosciences Cardiff University Museum Avenue Cardiff CF10 3AX United Kingdom

Brain Repair Group Sir Martin Evans Building School of Biosciences Cardiff University Museum Avenue Cardiff CF10 3AX United Kingdom; Central European Institute of Technology Institute of Anatomy Masaryk University A1 064 Kamenice 3 625 00 Brno Czech Republic

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

Department of Obstetrics and Gynaecology School of Medicine Cardiff University Cardiff CF14 4XN United Kingdom

Molecular Biosciences Research Division 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

Zobrazit více v PubMed

Arber C., Precious S.V., Cambray S., Risner-Janiczek J.R., Kelly C., Noakes Z., Fjodorova M., Heuer A., Ungless M.A., Rodriguez T.A., Rosser A.E., Dunnett S.B., Li M. Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. Development. 2015;142:1375–1386. PubMed PMC

Arlotta P., Molyneaux B.J., Chen J., Inoue J., Kominami R., Macklis J.D. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 2005;45:207–221. PubMed

Arlotta P., Molyneaux B.J., Jabaudon D., Yoshida Y., Macklis J.D. Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J. Neurosci. 2008;28:622–632. PubMed PMC

Aubry L., Bugi A., Lefort N., Rousseau F., Peschanski M., Perrier A.L. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc. Natl. Acad. Sci. U. S. A. 2008;105:16707–16712. PubMed PMC

Beal M.F., Kowall N.W., Ellison D.W., Mazurek M.F., Swartz K.J., Martin J.B. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature. 1986;321:168–171. PubMed

Carri A.D., Onorati M., Lelos M.J., Castiglioni V., Faedo A., Menon R., Camnasio S., Vuono R., Spaiardi P., Talpo F., Toselli M., Martino G., Barker R.A., Dunnett S.B., Biella G., Cattaneo E. Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32 + medium-sized spiny neurons. Development. 2013;140:301–312. PubMed

Davies S.W., Roberts P.J. No evidence for preservation of somatostatin-containing neurons after intrastriatal injections of quinolinic acid. Nature. 1987;327:326–329. PubMed

Davies S.W., Roberts P.J. Sparing of cholinergic neurons following quinolinic acid lesions of the rat striatum. Neuroscience. 1988;26:387–393. PubMed

Deacon T.W., Pakzaban P., Isacson O. The lateral ganglionic eminence is the origin of cells committed to striatal phenotypes: neural transplantation and developmental evidence. Brain Res. 1994;668:211–219. PubMed

Dunnett S.B., Bjorklund A., Oxford University P . 1992. Neural Transplantation a Practical Approach.

Ehrlich M.E., Rosen N.L., Kurihara T., Shalaby I.A., Greengard P. DARPP-32 development in the caudate nucleus is independent of afferent input from the substantia nigra. Brain Res. Dev. Brain Res. 1990;54:257–263. PubMed

Evans A.E., Kelly C.M., Precious S.V., Rosser A.E. Molecular regulation of striatal development: a review. Anaesth. Resusc. Intensive Ther. 2012;2012:106529. PubMed PMC

Ferland R.J., Cherry T.J., Preware P.O., Morrisey E.E., Walsh C.A. Characterisation of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. J. Comp. Neurol. 2003;460:266–279. PubMed

Harper P.S. Saunders Company Ltd.; 1996. Huntington's Disease: W.B.

Hisaoka T., Nakamura Y., Senba E., Morikawa Y. The forkhead transcription factors, Foxp1 and Foxp2, identify different subpopulations of projection neurons in the mouse cerebral cortex. Neuroscience. 2010;166:551–563. PubMed

Kelly C.M., Precious S.V., Penketh R., Amso N., Dunnett S.B., Rosser A.E. Striatal graft projections are influenced by donor cell type and not the immunogenic background. Brain. 2007;130:1317–1329. PubMed

Kelly C.M., Dunnett S.B., Rosser A.E. Medium spiny neurons for transplantation in Huntington's disease. Biochem. Soc. Trans. 2009;37:323–328. PubMed

Kelly C.M., Precious S.V., Torres E.M., Harrison A.W., Williams D., Scherf C., Weyrauch U.M., Lane E.L., Allen N.D., Penketh R., Amso N.N., Kemp P.J., Dunnett S.B., Rosser A.E. Medical terminations of pregnancy: a viable source of tissue for cell replacement therapy for neurodegenerative disorders. Cell Transplant. 2011;20:503–513. PubMed

Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. PubMed

Ma L., Hu B., Liu Y., Vermilyea S.C., Liu H., Gao L., Sun Y., Zhang X., Zhang S.C. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell. 2012;10:455–464. PubMed PMC

Olsson M., Campbell K., Wictorin K., Bjorklund A. Projection neurons in fetal striatal transplants are predominantly derived from the lateral ganglionic eminence. Neuroscience. 1995;69:1169–1182. PubMed

Precious S.V., Rosser A.E. Producing striatal phenotypes for transplantation in Huntington's disease. Exp. Biol. Med. 2012;237:343–351. PubMed

Rosser A.E., Kelly C.M., Dunnett S.B. Cell transplantation for Huntington's disease: practical and clinical considerations. Future Neurol. 2011;6:45–62.

Schwarcz R., Kohler C. Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci. Lett. 1983;38:85–90. PubMed

Schwarcz R., Whetsell W.O., Jr., Mangano R.M. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983;219:316–318. PubMed

Tamura S., Morikawa Y., Iwanishi H., Hisaoka T., Senba E. Expression pattern of the winged-helix/forkhead transcription factor Foxp1 in the developing central nervous system. Gene Expr. Patterns. 2003;3:193–197. PubMed

Tamura S., Morikawa Y., Iwanishi H., Hisaoka T., Senba E. Foxp1 gene expression in projection neurons of the mouse striatum. Neuroscience. 2004;124:261–267. PubMed

Urban N., Martin-Ibanez R., Herranz C., Esgleas M., Crespo E., Pardo M., Crespo-Enriquez I., Mendez-Gomez H.R., Waclaw R., Chatzi C., Alvarez S., Alvarez R., Duester G., Campbell K., de Lera A.R., Vicario-Abejon C., Martinez S., Alberch J., Canals J.M. Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling. Neural Dev. 2010;5:21. PubMed PMC

van der Kooy D., Fishell G. Neuronal birthdate underlies the development of striatal compartments. Brain Res. 1987;401:155–161. PubMed

Walaas S.I., Greengard P. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain. J. Neurosci. Off. J. Soc. Neurosci. 1984;4:84–98. PubMed PMC

Wang B., Weidenfeld J., Lu M.M., Maika S., Kuziel W.A., Morrisey E.E., Tucker P.W. Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development. 2004;131:4477–4487. PubMed