Development of the pharyngeal region depends on the interaction and integration of different cell populations, including surface ectoderm, foregut endoderm, paraxial mesoderm, and neural crest. Mice homozygous for a hypomorphic allele of Fgfr1 have craniofacial defects, some of which appeared to result from a failure in the early development of the second branchial arch. A stream of neural crest cells was found to originate from the rhombomere 4 region and migrate toward the second branchial arch in the mutants. Neural crest cells mostly failed to enter the second arch, however, but accumulated in a region proximal to it. Both rescue of the hypomorphic Fgfr1 allele and inactivation of a conditional Fgfr1 allele specifically in neural crest cells indicated that Fgfr1 regulates the entry of neural crest cells into the second branchial arch non-cellautonomously. Gene expression in the pharyngeal ectoderm overlying the developing second branchial arch was affected in the hypomorphic Fgfr1 mutants at a stage prior to neural crest entry. Our results indicate that Fgfr1 patterns the pharyngeal region to create a permissive environment for neural crest cell migration.[Keywords: Craniofacial development; fibroblast growth factor; branchial arch; hindbrain; neural crest; cell migration; cleft palate; Cre recombinase] Supplemental material is available at http://www.genesdev.org.

Stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), also known as ribosome-associated membrane protein 4 (RAMP4), is a Sec61-associated polypeptide that is induced by ER stress. SERP1؊/؊ mice, made by targeted gene disruption, demonstrated growth retardation, increased mortality, and impaired glucose tolerance. Consistent with high levels of SERP1 expression in pancreas, pancreatic islets from SERP1 ؊/؊ mice failed to rapidly synthesize proinsulin in response to a glucose load. In addition, reduced size and enhanced ER stress were observed in the anterior pituitary of SERP1 ؊/؊ mice, and growth hormone production was slowed in SERP1 ؊/؊ pituitary after insulin stimulation. Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1 ؊/؊ pancreas. In basal conditions, the Sec61 complex in SERP1 ؊/؊ microsomes was more cofractionated with ribosomes, compared with SERP1 ؉/؉ counterparts, in high-salt conditions. In contrast, after glucose stimulation, the complex showed less cofractionation at an early phase (45 min) but more at a later phase (120 min). Although intracellular insulin/proinsulin levels were not significantly changed in both genotypes, these results suggest that subtle changes in translocation efficiency play an important role in the regulation of ER stress and rapid polypeptide synthesis.Secretory proteins undergo posttranslational processing, including correct folding and oligomerization, in the endoplasmic reticulum (ER). In order to effectively produce and secrete mature proteins, cellular mechanisms for monitoring the ER environment are essential. In mammalian cells, at least three different mechanisms contribute to this surveillance system: regulated induction of transcription, attenuation of translation, and degradation (11). Exposure of cells to conditions promoting accumulation of unfolded proteins in the ER (ER stress) induces molecular chaperones, folding catalysts, and subunits of the translocation machinery (Sec61 complex), a process known as the unfolded protein response. Attenuation of protein synthesis in response to ER stress provides another point of regulation, in this case serving to reduce the load of proteins entering the ER. The latter pathway requires activation of the ER-resident membrane protein PERK and phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) (5).SERP1 (stress-associated ER protein 1) was identified because of its induction in response to hypoxia or ER stress (20) and found to be identical to RAMP4 (ribosome-associate membrane protein 4). The latter was originally recognized because it was copurified with the Sec61 complex (3, 19) and then found to be a genuine and evolutionarily conserved part of the ER translocon. SERP1/RAMP4 controls glycosylation of major histocompatibility complex class II-associated invariant chains by a translocational pausing mechanism (16), and its overexpression stabilizes newly synthesized membrane proteins under ER stress by ass...

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