Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis.

Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-α, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis.

The olfactory fascia: an evo-devo concept of the fibrocartilaginous nose.

PURPOSE: Evo-devo is the science that studies the link between evolution of species and embryological development. This concept helps to understand the complex anatomy of the human nose. The evo-devo theory suggests the persistence in the adult of an anatomical entity, the olfactory fascia, that unites the cartilages of the nose to the olfactory mucosa. METHODS: We dissected two fresh specimens. After resecting the superficial tissues of the nose, dissection was focused on the disarticulation of the fibrocartilaginous noses from the facial and skull base skeleton. RESULTS: Dissection shows two fibrocartilaginous sacs that were invaginated side-by-side in the midface and attached to the anterior skull base. These membranous sacs were separated in the midline by the perpendicular plate of the ethmoid. Their walls contained the alar cartilages and the lateral expansions of the septolateral cartilage, which we had to separate from the septal cartilage. The olfactory mucosa was located inside their cranial ends. CONCLUSION: The olfactory fascia is a continuous membrane uniting the nasal cartilages to the olfactory mucosa. Its origin can be found in the invagination and differentiation processes of the olfactory placodes. The fibrous portions of the olfactory fascia may be described as ligaments that unit the different components of the olfactory fascia one to the other and the fibrocartilaginous nose to the facial and skull base skeleton. The basicranial ligaments, fixing the fibrocartilaginous nose to the skull base, represent key elements in the concept of septorhinoplasty by disarticulation.

Shaping skeletal growth by modular regulatory elements in the Bmp5 gene.

Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body.

[Chondroblast proliferative activity study in forming big alar cartilage].

Study was performed of chondroblast proliferative activity peculiarities on early stages of big alar cartilage forming. The reaction with monoclonal antibodies towards proliferating cell nuclear antigen in alar cartilage of human embryo and newly born infant rat testified to 2 cartilage growth types - appositional and interstitial. Cells proliferative activity did not depend upon their location on inner or outer side of nasal cartilaginous plate thereby not conforming existent in the literature opinion about the presence of special zones of cartilaginous tissue primary new formation in human nasal cartilage on early stages of its ontogeny.

Prenasal thickness to nasal bone length ratio: effectiveness as a second or third trimester marker for Down syndrome.

OBJECTIVE: To assess the value of the prenasal thickness to nasal bone length ratio (PT/NBL) for detecting trisomy 21 (T21) after the first trimester. METHOD: Two examiners blinded to fetal T21 status retrospectively measured prenasal thickness (PT) and nasal bone length (NBL) of T21 and control fetuses at 15-36 weeks' gestational age on two-dimensional images from all T21-screening ultrasounds from November 2010 to April 2013. ROC curve analysis and its diagnostic values determined the best cut-off value for the ratio. Interobserver reproducibility was assessed. RESULTS: Good quality ultrasound profile images were available for 26 fetuses with T21 compared to 91 normal fetuses. The median PT/NBL ratio was 1.28 for T21 and 0.73 for control fetuses (p<0.0001). The PT/NBL ratio performed significantly better (AUC 0.99; 95%CI 0.97-1) than either PT (0.82; 0.73-0.91) or NBL (0.91; 0.85-0.98). The optimal PT/NBL ratio cut-off was 0.98, with a sensitivity of 88.5% [76.2-100%] and a specificity of 100%. Interobserver variability was low. CONCLUSION: The PT/NBL ratio is a strong marker for detecting T21 in the second and third trimesters, significantly more effective than either indicator alone.

Revisiting human nose anatomy: phylogenic and ontogenic perspectives.

This review suggests revisiting nose anatomy by considering the ethmoidal labyrinths as part of the olfactory nose and not as paranasal sinuses. Phylogenetically, the olfactory and respiratory organs of the most primitive vertebrates are separated. Exaptation, a mechanism of evolution, may explain the fusion of the olfactory and respiratory organs in dipnoi. The respiratory and olfactory noses remain anatomically separated by the transverse lamina in most mammals, whose olfactory labyrinth is a blind recess housing the ethmoturbinates. In humans, the partitioning between the olfactory cleft and the ethmoid labyrinth seems to be a consequence of ethmoid bone remodeling induced by the acquisition of an upright posture. The ethmoid bone is derived from the cartilaginous nasal capsule of primitive vertebrates and considered to be a highly conserved region among the bony elements of the skull base. It appears to be involved only in housing and protecting the olfactory function. During the early stages of human fetal development, rupture of the oronasal membrane leads to the integration of the primary olfactory sac in the future respiratory organ. The cartilaginous nasal capsule appears in the tissue under the brain and around the olfactory channels. Its early fetal development is classically regarded as the beginning of paranasal sinus formation. From phylogenic and ontogenic perspectives, it may be regarded as the development of the olfactory labyrinth as modified by the remodeling process of the human face and skull base. The endochondral bony origin of the ethmoid labyrinths makes them substantially different from the other paranasal sinuses.