The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum

Abstract

Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO),which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1-/- embryos, the mes/met is deleted by the 30 somite stage (∼E10) (McMahon, A. P. and Bradley, A.(1990) Cell 62,1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage (∼E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes,and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.

A Role for Receptor Protein Tyrosine Phosphatase in Midbrain Development

“…This raises the possibility that tight, local regulation of Ras-MAP kinase activity may be a prerequisite for Wnt1 expression at the MHB and that RPTP may contribute to this regulation through modulation of Ras-MAP kinase signaling. Notably, in mouse embryos in which Fgf8 expression was specifically lost in the MHB territory from the five somite stage onwards, the transverse ring of Wnt1 expression in the caudal mesencephalon was also absent, whereas the expression domains of Fgf8, Otx2, Pax2, or En1 appeared normal at early stages of embryogenesis (Chi et al, 2003). Genetic loss of Fgf8 at the MHB, however, caused massive cell death, an effect we did not observe within 24 h after RPTP transfection.…”

Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

“…FGF8b induces cerebellar tissue whereas FGF8a induces midbrain structures (Lee et al, 1997;Liu et al, 1999Liu et al, , 2003Sato et al, 2001). Moreover, mutants that express low levels of FGF8 only develop the superior colliculus and lateral cerebellum structures (Chi et al, 2003). Thus, in light of the finding that the source of FGF8 signaling is shifted further away from the presumptive cerebellar primordium in Hoxb.7-Cre;SuFu Ϫ/loxP mutants, it is likely that levels of FGF8 are reduced in comparison with wild-type tissue.…”

Functional evolutionary history of the mouse Fgf gene family

“…Other Fgf knockout mice either are viable or die during postnatal stages (Table 1). Conditional knockouts of Fgfs that have essential roles early in development have also revealed important functions for these Fgfs at later times of development Sun et al, 2000;Chi et al, 2003;Lewandoski et al, 2000).…”