Skip to main content

Advertisement

SpringerLink
Log in

Fgf15 regulates thalamic development by controlling the expression of proneural genes

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

The establishment of the brain structural complexity requires a precisely orchestrated interplay between extrinsic and intrinsic signals modulating cellular mechanisms to guide neuronal differentiation. However, little is known about the nature of these signals in the diencephalon, a complex brain region that processes and relays sensory and motor information to and from the cerebral cortex and subcortical structures. Morphogenetic signals from brain organizers regulate histogenetic processes such as cellular proliferation, migration, and differentiation. Sonic hedgehog (Shh) in the key signal of the ZLI, identified as the diencephalic organizer. Fgf15, the mouse gene orthologous of human, chick, and zebrafish Fgf19, is induced by Shh signal and expressed in the diencephalic alar plate progenitors during histogenetic developmental stages. This work investigates the role of Fgf15 signal in diencephalic development. In the absence of Fgf15, the complementary expression pattern of proneural genes: Ascl1 and Nng2, is disrupted and the GABAergic thalamic cells do not differentiate; in addition dorsal thalamic progenitors failed to exit from the mitotic cycle and to differentiate into neurons. Therefore, our findings indicate that Fgf15 is the Shh downstream signal to control thalamic regionalization, neurogenesis, and neuronal differentiation by regulating the expression and mutual segregation of neurogenic and proneural regulatory genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

avLGN:

Anterior ventral lateral geniculate nucleus

Chp:

Choroid plexus

CNS:

Central nervous system

dLGN:

Dorsal lateral geniculate nucleus

Di:

Diencephalon

ETh:

Epithalamus

Fgf:

Fibroblast growth factor

FgfR:

Fibroblast growth factor receptor

Hy:

Hypothalamus

IGL:

Intergeniculate leaflet

LHb:

Lateral habenula

LGN:

Lateral geniculate nucleus

M:

Mesencephalon

p2ZLI:

Prosomer 2 zona limitans intrathalamica

p3ZLI:

Prosomer 3 zona limitans intrathalamica

pg:

Pineal gland

pvLGN:

Posterior ventral lateral geniculate nucleus

pTh-R:

Rostral thalamic ventricular zone

PTh:

Prethalamus

PThE:

Eminentia thalami

rft:

Retroflexus tract

Th:

Thalamus

vLGN:

Ventral lateral geniculate nucleus

ZLI:

Zona limitans intrathalamica

References

  • Anderson SA, Marín O, Horn C, Jennings K, Rubenstein JLR (2001) Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128(3):353–363

    CAS  PubMed  Google Scholar 

  • Borello U, Cobos I, Long JE, McWhirter JR, Murre C, Rubenstein JL (2008) FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development. Neural Dev 3:17

    Article  PubMed  PubMed Central  Google Scholar 

  • Chatterjee M, Li K, Chen L, Maisano X, Guo Q, Gan L, Li JY (2012) Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes. Development 139(24):4633–4643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Li X, Eswarakumar VP, Seger R, Lonai P (2000) Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt-PKB is required for embryoid body differentiation. Oncogene 19:3750–3756

    Article  CAS  PubMed  Google Scholar 

  • Chi CL, Martinez S, Wurst W, Martin GR (2003) The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum. Development 130(12):2633–2644

    Article  CAS  PubMed  Google Scholar 

  • Crossley PH, Martin GR (1995a) The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121:439–451

    CAS  PubMed  Google Scholar 

  • Crossley PH, Martin GR (1995b) The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that directs outgrowth and patterning in the developing embryo. Development 121(2):439–451

    CAS  PubMed  Google Scholar 

  • Delaunay D, Heydon K, Miguez A, Schwab M, Nave K-A, Thomas JL, Spassky N, Martinez S, Zalc B (2009) Genetic tracing of subpopulation neurons in the prethalamus of mice (Mus musculus). J Comp Neurol 512:74–83

    Article  PubMed  Google Scholar 

  • Dickinson M, McMahon A (1992) The role of Wnt genes in vertebrate development. Curr Opin Genet Dev 2:562–566

    Article  CAS  PubMed  Google Scholar 

  • Echelard Y, Epstein D, St-Jacques B, Shen L, Mohler J, McMahon J, McMahon A (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417–1430

    Article  CAS  PubMed  Google Scholar 

  • Epstein DJ (2012) Regulation of thalamic development by sonic hedgehog. Front Neurosci 6:57

    Article  PubMed  PubMed Central  Google Scholar 

  • Fischer T, Faus-Kessler T, Welzl G, Simeone A, Wurst W, Prakash N (2011) Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis. Dev Biol 350:496–510

    Article  CAS  PubMed  Google Scholar 

  • Ford-Perriss M, Abud H, Murphy M (2001) Fibroblast growth factors in the developing central nervous system. Clin Exp Pharmacol Physiol 28:493–503

    Article  CAS  PubMed  Google Scholar 

  • Garel S, Huffman KJ, Rubenstein JLR (2003) Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development 130:1903–1914

    Article  CAS  PubMed  Google Scholar 

  • Gimeno L, Martinez S (2007) Expression of chick Fgf19 and mouse Fgf15 orthologs is regulated in the developing brain by Fgf8 and Shh. Dev Dyn 236:2285–2297

    Article  CAS  PubMed  Google Scholar 

  • Gimeno L, Brûlet P, Martinez S (2003) Study of Fgf15 gene expression in developing mouse brain. Gene Expr Patterns 3:473–481

    Article  CAS  PubMed  Google Scholar 

  • Golding B, Pouchelon G, Bellone C, Murthy S, Nardo AAD, Govindan S, Ogawa M, Shimogori T, Lüscher C, Dayer A et al (2014) Retinal input directs the recruitment of inhibitory interneurons into thalamic visual circuits. Neuron 81(5):1057–1069

    Article  CAS  PubMed  Google Scholar 

  • Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL (2004) The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry 43:629–640

    Article  CAS  PubMed  Google Scholar 

  • Inamura N, Ono K, Takebayashi H, Zalc B, Ikenaka K (2011) Olig2 lineage cells generate GABAergic neurons in the prethalamic nuclei, including the zona incerta, ventral lateral geniculate nucleus and reticular thalamic nucleus. Dev Neurosci 33:118–129

    Article  CAS  PubMed  Google Scholar 

  • Inverardi F, Beolchi MS, Ortino B, Moroni RF, Regordi MC, Amadeo A, Frassoni C (2007) GABA immunoreactivity in the developing rat thalamus and Otx2 homeoprotein expression in migrating neurons. Brain Res Bull 73:64–74

    Article  CAS  PubMed  Google Scholar 

  • Ishibashi M (2004) Molecular mechanisms for morphogenesis of the central nervous system in mammals. Anat Sci Int 79:226–34

    Article  CAS  PubMed  Google Scholar 

  • Ishibashi M, McMahon AP (2002) A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo. Development 129:4807–4819

    CAS  PubMed  Google Scholar 

  • Jeong Y, Dolson DK, Waclaw RR, Matise MP, Sussel L, Campbell K, Kaestner KH, Epstein DJ (2011) Spatial and temporal requirements for sonic hedgehog in the regulation of thalamic interneuron identity. Development 138:531–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones EG (1985) The thalamus. Springer, Plenum Press, New York

  • Jones S (2007) Mini-review: endocrine actions of fibroblast growth factor 19. Mol Pharm 5:42–48

    Article  Google Scholar 

  • Kang W, Wong LC, Shi SH, Hébert JM (2009) The transition from radial glial to intermediate progenitor cell is inhibited by FGF signaling during corticogenesis. J Neurosci 29:14571–14580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kataoka A, Shimogori T (2008) Fgf8 controls regional identity in the developing thalamus. Development 135(17):2873–2881

    Article  CAS  PubMed  Google Scholar 

  • Kiecker C, Lumsden A (2004) Hedgehog signaling from the ZLI regulates diencephalic regional identity. Nat Neurosci 7:1242–1249

    Article  CAS  PubMed  Google Scholar 

  • Kingsley D (1994) The TGF-beta superfamily: new members, new receptors and new genetic tests of function in different organisms. Genes Dev 8:133–146

    Article  CAS  PubMed  Google Scholar 

  • Kitamura K, Miura H, Yanazawa M, Miyashita T, Kato K (1997) Expression patterns of Brx1 (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear formation. Mech Dev 67:83–96

    Article  CAS  PubMed  Google Scholar 

  • Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60(4):585–595

    Article  CAS  PubMed  Google Scholar 

  • Martinez S, Crossley PH, Cobos I, Rubenstein JLR, Martin GR (1999) FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126(6):1189–1200

    CAS  PubMed  Google Scholar 

  • Martinez-Ferre A, Martinez S (2009) The development of the thalamic motor learning area is regulated by Fgf8 expression. J Neurosci 29(42):13389–13400

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Ferre A, Martinez S (2012) Molecular regionalization of the diencephalon. Front Neurosci 6:73

    Article  PubMed  PubMed Central  Google Scholar 

  • Martinez-Ferre A, Navarro-Garberi M, Bueno C, Martinez S (2013) Wnt signal specifies the intrathalamic limit and its organizer properties by regulating Shh induction in the alar plate. J Neurosci 33(9):3967–3980

    Article  CAS  PubMed  Google Scholar 

  • Mason I (2007) Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat Rev Neurosci 8:583–596

    Article  CAS  PubMed  Google Scholar 

  • Miyake A, Nakayama Y, Konishi M, Itoh N (2005) Fgf19 regulated by Hh signaling is required for zebrafish forebrain development. Dev Biol 288(1):259–275

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Bravo JA, Perez-Balaguer A, Martinez-Lopez JE, Aroca P, Puelles L, Martinez S, Puelles E (2014) Role of Shh in the development of molecularly characterized tegmental nuclei in mouse rhombomere 1. Brain Struct Funct 219:777–792

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa Y, O’Leary DDM (2001) Combinatiorial expression patterns of LIM-homeodomain and other regulatory genes parcellate developing thalamus. J Neurosci 21(8):2711–2725

    CAS  PubMed  Google Scholar 

  • Nakagawa Y, Shimogori T (2012) Diversity of thalamic progenitor cells and postmitotic neurons. Eur J Neurosci 35(10):1554–1562

    Article  PubMed  Google Scholar 

  • Nakamura H, Sato T, Suzuki-Hirano A (2008) Isthmus organizaer for mesencephalon and metencephalon. Dev Growth Differ 50(Suppl 1):113–118

    Article  Google Scholar 

  • Niehrs C, Meinhardt H (2002) Modular feedback. Nature 417:35–36

    Article  CAS  PubMed  Google Scholar 

  • Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I (2001) Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci USA 98:6074–6079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ortino B, Inverardi F, Morante-Oria J, Fairén A, Frassoni C (2003) Substrates and routes of migration of early generated neurons in the developing rat thalamus. Eur J Neurosci 18(2):323–332

    Article  PubMed  Google Scholar 

  • Ottersen OP, Storm-Mathisen J (1984) Glutamate- and GABA-containing neurons in the mouse and rat brain, as demonstrated with a new immunocytochemical technique. J Comp Neurol 229(3):374–392

    Article  CAS  PubMed  Google Scholar 

  • Peukert D, Weber S, Lumsden A, Scholpp S (2011) Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signaling. PLOS Biol 9(12):e1001218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puelles L, Martinez S (2013) Patterning of the diencephalon, in the patterning and cell type specification in the developing CNS and PNS. John Rubenstein and Pasko Rakic. Elsevier, Amsterdam

    Google Scholar 

  • Puelles E, Acampora D, Gogoi R, Tuorto F, Papalia A, Guillemot F, Ang S-L, Simeone A (2006) Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation. J Neurosci 26(22):5955–5964

    Article  CAS  PubMed  Google Scholar 

  • Roybon L, Mastracci TL, Ribeiro D, Sussel L, Brundin P, Li JY (2010) GABAergic differentiation induced by Mash1 is compromised by the bHLH proteins Neurogenin2, NeuroD1, and NeuroD2. Cereb Cortex 5:1234–1244

    Article  Google Scholar 

  • Sato T, Joyner AL (2009) The duration of Fgf8 isthmic organizer expression is key to patterning different tectal-isthmo-cerebellum structures. Development 136(21):3617–3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scholpp S, Wolf O, Brand M, Liumsden A (2006) Hedgehod sinalling from the zona limitans intrathalamica orchestrates patterning of the zebrafish diencephalon. Development 133:855–864

    Article  CAS  PubMed  Google Scholar 

  • Scholpp S, Delogu A, Gilthorpe J, Peukert D, Schindler S, Lumsden A (2009) Her6 regulates the neurogenetic gradient and neuronal identity in the thalamus. Proc Natl Acad Sci USA 24:19895–19900

    Article  Google Scholar 

  • Simeone A, Acampora D, Mallamaci A, Stornaiuolo A, D’Apice MR, Nigro V, Boncinelli E (1993) A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J 12:2735–27747

    CAS  PubMed  PubMed Central  Google Scholar 

  • Storm EE, Garel S, Borello U, Hebert JM, Martinez S, McConnell SK, Martin GR, Rubenstein JL (2006) Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133:1831–1844

    Article  CAS  PubMed  Google Scholar 

  • Theiler K (1989) The house mouse. Atlas of embryonic development. Springer, New York

    Book  Google Scholar 

  • Vieira C, Martinez S (2006) Sonic hedgehog from the basal plate and the zona limitans intrathalamica exhibits differential activity on diencephalic molecular regionalization and nuclear structure. Neurosci 143:129–140

    Article  CAS  Google Scholar 

  • Virolainen SM, Achim K, Peltopuro P, Salminen M, Partanen J (2012) Transcriptional regulatory mechanisms underlying the GABAergic neuron fate in different diencephalic prosomeres. Development 139(20):3795–3805

    Article  CAS  PubMed  Google Scholar 

  • Vue TY, Aaker J, Taniguchi A, Kazemzadeh C, Skidmore JM, Martin DM, Martin JF, Treier M, Nakagawa Y (2007) Characterization of progenitor domains in the developing mouse thalamus. J Comp Neurol 505:73–91

    Article  CAS  PubMed  Google Scholar 

  • Vue TY, Bluske K, Alishahi A, Yang LL, Koyano-Nakagawa N, Novitch B, Nakagawa Y (2009) Sonic hedgehog signaling controls thalamic progenitor identity and nuclei specification in mice. J Neurosci 29(19):4484–4497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolpert L (2011) Positional information and patterning revisited. J Theor Biol 269(1):359–365

    Article  PubMed  Google Scholar 

  • Wright TJ, Ladher R, McWhirter J, Murre C, Schoenwolf GC, Mansour SL (2004) Mouse FGF15 is the orgholog of human and chick FGF19, but is not uniquely required for otic induction. Dev Biol 269:264–275

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the following Grants: European consortium EUCOMMTOOLS (Contract HEALTH-FA-2010-261492), Spanish Ministry of Science and Innovation Grant BFU-2011-27326, Consolider Grant CSD2007-00023, Institute of Health Carlos III, Spanish Cell Therapy Network and Research Center of Mental Health, and General Council of Valencia (Prometeo 2009/028 and 11/2011/042). We thank M. Ródenas and F. Almagro for technical assistance.

Author information

Authors and Affiliations

  1. Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), University of Murcia, 30120, El Palmar, Murcia, Spain

    Almudena Martinez-Ferre & Salvador Martinez

  2. Institute of Neurosciences, Miguel Hernández University, Spanish National Research Council, San Juan Campus, 03550, Sant Joan d’Alacant, Alicante, Spain

    Cosme Lloret-Quesada & Salvador Martinez

  3. Institute of Developmental Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health (GmbH), Technical University Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany

    Nilima Prakash & Wolfgang Wurst

  4. Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA, USA

    John L. R. Rubenstein

  5. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Valencia, Spain

    Salvador Martinez

Authors
  1. Almudena Martinez-Ferre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cosme Lloret-Quesada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nilima Prakash
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Wurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John L. R. Rubenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Salvador Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvador Martinez.

Electronic supplementary material

Below is the link to the electronic supplementary material.

429_2015_1089_MOESM1_ESM.pdf

Supplementary Fig. 1: (a-c) Diencephalic expression of Fgf8 at E11.5 mouse embryo. The ISH signal was localized exclusively in the most dorsal domain of the alar plate and the roof plate of prethalamus (PTh) and thalamus (Th). The ZLI do not shows signal. (d-i) Expression of Fgf15 (d,g) , Fgfr3 (e,h) and Fgfr2 (f,i) in the diencephalon of E11.5 (d-f) and E13.5 (g,i) mouse embryos. Arrows are labeling the localization of the ZLI. The images have been captured from the Allen brain Atlas/Developing mouse brain project data-base at http://www.brain-map.org (PDF 7054 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martinez-Ferre, A., Lloret-Quesada, C., Prakash, N. et al. Fgf15 regulates thalamic development by controlling the expression of proneural genes. Brain Struct Funct 221, 3095–3109 (2016). https://doi.org/10.1007/s00429-015-1089-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-015-1089-5

Keywords

Search

Navigation