Background The role of fibroblast growth factor and receptor (FGF/FGFR) signaling in bone development is well studied, partly because mutations in FGFRs cause human diseases of achondroplasia and FGFR-related craniosynostosis syndromes including Crouzon syndrome. The FGFR2c C342Y mutation is a frequent cause of Crouzon syndrome, characterized by premature cranial vault suture closure, midfacial deficiency and neurocranial dysmorphology. Here, using newborn Fgfr2cC342Y/+ Crouzon syndrome mice, we tested whether the phenotypic effects of this mutation go beyond the skeletal tissues of the skull, altering the development of other non-skeletal head tissues including the brain, the eyes, the nasopharynx and the inner ears. Results Quantitative analysis of 3D multimodal imaging (high resolution micro computed tomography and magnetic resonance microscopic images) revealed local differences in skull morphology and coronal suture patency between Fgfr2cC342Y/+ mice and unaffected littermates, as well as changes in brain shape but not brain size, significant reductions in nasopharyngeal and eye volumes, and no difference in inner ear volume in Fgfr2cC342Y/+ mice. Conclusion These findings provide an expanded catalogue of clinical phenotypes in Crouzon syndrome caused by aberrant FGF/FGFR signaling and evidence of the broad role for FGF/FGFR signaling in development and evolution of the vertebrate head.

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system. We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice. The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

Craniofacial and neural tissues develop in concert throughout pre- and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for Apert syndrome using the Fgfr2+/P253R mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2+/P253R mice and unaffected littermates at P0 (N=28) and P2 (N=23). 3D coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2+/P253R mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other.

Calcitonin (CT) is primarily produced by the thyroid C cells in mammals or by the ultimobranchial gland in chickens. CT is also expressed by the pituitary gland in rats in which it functions as a paracrine factor causing decreased lactotroph proliferation and prolactin (PRL) secretion. Gonadal steroids influence CT expression in the rat pituitary gland. However, the expression of the CT gene in the pituitary gland of chickens or of any other avian species has not previously been reported. We have tested the hypotheses that CT is expressed in the chicken pituitary gland, and that its expression is influenced by sexual maturation or in response to ovarian steroid administration. We have detected robust expression of CT cDNA in the chicken pituitary gland by reverse transcription/polymerase chain reaction (PCR). The sequence of the pituitary-derived CT cDNA is identical to that of the ultimobranchial gland. CT-immunoreactive (ir) cells have been observed throughout the anterior pituitary gland by confocal microscopy. Many of the PRL-ir cells show co-localization with CT-ir cells. Quantitative real-time PCR analysis has revealed an inverse relationship between the quantities of PRL mRNA and CT mRNA in the pituitary gland: sexually mature hens contain lower amounts of CT mRNA but larger quantities of PRL mRNA compared with sexually immature chickens. Estradiol and/or progesterone treatment of sexually immature chickens leads to a significant decrease in the quantity of pituitary CT mRNA relative to that in the vehicle-treated chickens. We conclude that pituitary CT plays an important paracrine/autocrine role in the control of lactotroph function and PRL secretion in the chicken.

COVER PHOTOGRAPH: Multimodal imaging and segmentation used to visualize skull (yellow), brain (pink), inner ear (green), nasopharynx (green) and globe of the eye (blue) in Fgfr2cC342Y/+Crouzon syndrome mice (top) and normal littermates (bottom). From Martínez‐Abadías et al., Developmental Dynamics 242:80–94, 2013.