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Fgf15 regulates thalamic development by controlling the expression of proneural genes

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.

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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

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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.

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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)

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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

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Keywords

  • Diencephalon
  • Thalamus
  • Regionalization
  • ZLI
  • Fgf15
  • Shh