Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch

Abstract

In mammals, the first branchial arch (BA1) develops into a number of craniofacial skeletal elements including the jaws and teeth. Outgrowth and patterning of BA1 during early embryogenesis is thought to be controlled by signals from its covering ectoderm. Here we used Cre/loxP technology to inactivate the mouse Fgf8 gene in this ectoderm and have obtained genetic evidence that FGF8 has a dual function in BA1: it promotes mesenchymal cell survival and induces a developmental program required for BA1 morphogenesis. Newborn mutants lack most BA1-derived structures except those that develop from the distal-most region of BA1, including lower incisors. The data suggest that the BA1 primordium is specified into a large proximal region that is controlled by FGF8, and a small distal region that depends on other signaling molecules for its outgrowth and patterning. Because the mutant mice resemble humans with first arch syndromes that include agnathia, our results raise the possibility that some of these syndromes are caused by mutations that affect FGF8 signaling in BA1 ectoderm.

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

“…Previously, we showed genetic interaction between Shh and Ndst1 and reduced Ptc expression in facial Ndst1 Ϫ/Ϫ mesenchyme as well as strongly reduced MAPK activity after Fgf-2 stimulation of Ndst1 Ϫ/Ϫ mesenchymal fibroblasts (Grobe et al, 2005). In this work, we confirmed impaired Fgf function in the developing mutant skull in agreement with the established role of Fgf-8 in skull and facial development (Meyers et al, 1998;Trumpp et al, 1999;Abu-Issa et al, 2002;Frank et al, 2002). Notably, Fgf-8 mutants also share neural and limb defects similar to those found in Ndst1 mutant embryos.…”

21st Century neontology and the comparative development of the vertebrate skull

“…This model expands on an evolving model of polarity within the mandibular arch (e.g., Sharpe, 1995;Neubuser et al, 1997;Thomas et al, 1998Thomas et al, , 2002Tucker et al, 1998Tucker et al, , 1999Trumpp et al, 1999) and seeks to explain a developmental patterning system that apparently keeps gnathostome jaws in functional registration yet tractable to potential changes in functional demands over evolutionary time. It relies upon a system for the establishment of positional information where pattern and placement of the "hinge" is driven by factors common to the junction of mxBA1 and mdBA1 and of the "caps" (i.e., signals from the primordia of "other furthestfrom-hinge" of above) by the signals emanating from the distal-most BA1 midline and the lambdoidal junction (where the mxBA1 meets the olfactory placode-associated FNP).…”

“…To (1) make sense of these possibilities and (2) form a foundation for which a comparison between and within taxa can eventually be framed, a hypothesis for jaw development is useful. To this end, we present here a "hinge and caps" model that places the articulation, and subsequently the polarity and modularity, of the upper and lower murine jaws in the context of CNC competence to respond to positionally located epithelial signals (Depew et al, 1999(Depew et al, , 2002a(Depew et al, ,b, 2005Trumpp et al, 1999;Shigetani et al, 2000Shigetani et al, , 2002.…”

“…Further transformations about the hinge are seen with the targeted disruption of both the endothelin signaling pathway and its potential targets, the nested Dlx5 and Dlx6 genes (Kurihara et al, 1994;Clouthier et al, 1998;Yanagisawa et al, 1998;Acampora et al, 1999;Depew et al, 1999;Charite et al, 2001;Ruest et al, 2004). Dlx5 is expressed both in early head mesenchyme (mdBA1 CNC) and epithelia (e.g., the early anterior cephalic ectoderm, ANR, and olfactory and otic placodes; Simeone et al, 1994;Qiu et al, 1997;Yang et al, 1998;Depew et al, 1999).…”

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

“…In order to examine the role of Dnmt3a in the nervous system, we crossed Dnmt3a conditional knockout mice to the Nes-Cre1 transgenic line (Bates et al, 1999;Trumpp et al, 1999;Dubois et al, 2006), in which a modified Cre recombinase transgene is under the control of the rat nestin promoter and intron 2 enhancer. The Nes-Cre1 transgene has been shown to cause complete or near-complete deletion of various loci in the central nervous system by E15.5 (Dubois et al, 2006).…”