FGF regulated gene-expression and neuronal differentiation in the developing midbrain–hindbrain region

Abstract

The neuroectodermal tissue close to the midbrain-hindbrain boundary (MHB) is an important secondary organizer in the developing neural tube. This so-called isthmic organizer (IsO) secretes signaling molecules, such as fibroblast growth factors (FGFs), which regulate cellular survival, patterning and proliferation in the midbrain and rhombomere 1 (R1) of the hindbrain. We have previously shown that FGF-receptor 1 (FGFR1) is required for the normal development of this brain region in the mouse embryo. Here, we have compared the gene expression profiles of midbrain-R1 tissues from wild-type embryos and conditional Fgfr1 mutants, in which FGFR1 is inactivated in the midbrain and R1. Loss of Fgfr1 results in the downregulation of several genes expressed close to the midbrain-hindbrain boundary and in the disappearance of gene expression gradients in the midbrain and anterior hindbrain. Our screen identified several previously uncharacterized genes which may participate in the development of midbrain-R1 region. Our results also show altered neurogenesis in the midbrain and R1 of the Fgfr1 mutants. Interestingly, the neuronal progenitors in midbrain and R1 show different responses to the loss of signaling through FGFR1.

Dynamic expression of Thyrotropin‐releasing hormone in the mouse definitive endoderm

“…At this stage, we begin to see expression in the developing neural tissues, specifically at the midbrain-hindbrain junction and in the posterior neural tube. A recently published report has described Trh expression from E8.0 to E10.5 (Jukkola et al, 2006). In agreement with our data, this analysis also observed Trh expression in the developing neural folds, although at slightly earlier stages than in our analysis.…”

“…The presence of TRH throughout the central nervous system as well as in numerous peripheral organs supports a diverse range of roles for this molecule outside of the traditional HPT axis, including a potential role as a neurotransmitter. During mouse embryogenesis, Trh mRNA has been detected in the neural folds at E8.0, at the midbrain-hindbrain junction from E8.5 to E10.5, and in the developing hypothalamus from E11.5 to E18.5 (Schonemann et al, 1995;Michaud et al, 1998Michaud et al, , 2000Acampora et al, 1999;Wang and Lufkin, 2000;Keith et al, 2001;Backman et al, 2003;Goshu et al, 2004;Caqueret et al, 2006;Jukkola et al, 2006). Despite the critical role of TRH in regulating the HPT axis and its expression in developing neural structures, mice deficient in Trh are viable and fertile (Yamada et al, 1997(Yamada et al, , 2003.…”

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).…”

Gestational stress induces the unfolded protein response, resulting in heart defects

“…This suggests that the Fgf8 gene might itself be a target of FGF signaling, and that its reduced transcription is a consequence, rather than the cause, of reduced FGF signaling. This is supported by the observation that conditional knockout of Fgfr1 in the midbrain-hindbrain boundary greatly reduces FGF signaling and abolishes Fgf8 expression (Jukkola et al, 2006). We next examined FGFR1 protein expression.…”