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doi: 10.1242/10.1242/dev.00487
1 Department of Anatomy and Program in Developmental Biology, School of
Medicine, University of California at San Francisco, San Francisco, CA
94143-0452, USA
2 Institute of Neurosciences, University Miguel Hernandez, San Juan, Alicante,
Spain 03550
3 GSF-Research Center, Institute for Developmental Genetics, 85764
Munich/Neuherberg, Max Planck Institute of Psychiatry, 80804 Munich,
Germany
* Author for correspondence (e-mail: gmartin{at}itsa.ucsf.edu)
Accepted 6 March 2003
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.
Key words: Brain patterning, Cerebellum, Fgf8, Isthmic organizer, mes/met, Mesencephalon, Metencephalon, Midbrain, Midbrain/hindbrain organizer, Mouse, Rhombomere 1
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