FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals

Abstract

Fibroblast growth factors (FGFs) are signaling molecules of the isthmic organizer, which regulates development of the midbrain and cerebellum. Tissuespeci®c inactivation of one of the FGF receptor (FGFR) genes, Fgfr1, in the midbrain and rhombomere 1 of the hindbrain of mouse embryos results in deletion of the inferior colliculi in the posterior midbrain and vermis of the cerebellum. Analyses of both midbrain±hindbrain and midbrain-speci®c Fgfr1 mutants suggest that after establishment of the isthmic organizer, FGFR1 is needed for continued response to the isthmic signals, and that it has direct functions on both sides of the organizer. In addition, FGFR1 appears to modify cell adhesion properties critical for maintaining a coherent organizing center. This may be achieved by regulating expression of speci®c cell-adhesion molecules at the midbrain±hindbrain border.

Fibroblast Growth Factor Receptors Cooperate to Regulate Neural Progenitor Properties in the Developing Midbrain and Hindbrain

“…Consistently, conditional inactivation of Fgfr1 results in midbrain and r1 defects (Trokovic et al, 2003(Trokovic et al, , 2005Jukkola et al, 2006), whereas inactivation of Fgfr2 or Fgfr3 alone does not interfere with the development of this brain region (Blak et al, 2006). Compared with the conditional Fgf8 mutants, however, the phenotype of the conditional Fgfr1 mutants is clearly less severe (Trokovic et al, 2003;Jukkola et al, 2006).…”

“…Compared with the conditional Fgf8 mutants, however, the phenotype of the conditional Fgfr1 mutants is clearly less severe (Trokovic et al, 2003;Jukkola et al, 2006). Target genes of FGF signaling are still expressed in the midbrain and r1 of the Fgfr1 mutants, except in the cells near the midbrain-r1 border (Trokovic et al, 2003(Trokovic et al, , 2005. Because these regions overlap with Fgfr2 and Fgfr3 expression, it is possi-ble that in Fgfr1 mutants, either FGFR2, FGFR3, or both mediate residual FGF signaling.…”

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

“…Mice carrying one copy of the Nestin-CreER allele and one copy of the FGFR3 GOF allele from transgenic founder line 10, which expressed intermediate levels of protein upon recombination, were used for all experiments. The mutant Fgfr, Nestin-CreER, Rosa26 lox-stop-lox-EGFP reporter, and CamK2a-CreER mice were described previously (17,18,(42)(43)(44)(45)(46). Two-to three-month-old adult mice were used at the start of each experiment.…”

Analysis of the midbrain–hindbrain boundary cell fate using a boundary cell‐specific Cre‐mouse strain

“…In situ hybridization was performed with [ 35 S]UTP-labeled probes, using standard procedures (Wilkinson and Green, 1990). Probes used for in situ analysis were Otx2 (Acampora et al, 1997), p21 (Trokovic et al, 2005), and PB-cadherin (Trokovic et al, 2003).…”

“…In addition to the signaling function, several studies have given strong support for cell-lineage restriction and prevention of cell mixing across midbrain-hindbrain boundary (Langenberg and Brand, 2005;Millet et al, 1996;Zervas et al, 2004). The presence of boundaryspecific cell adhesion molecules (PB-cadherin, Kitajima et al, 1999;Trokovic, 2003) as well as cell cycle regulators (p21, Trokovic et al, 2005) implicates that a subpopulation of IsO cells closest to the midbrain-hindbrain boundary might have a unique identity. Here we report generation of transgenic mouse line expressing the Cre-recombinase in a boundary cell-specific fashion.…”