Neural crest-specific loss ofBmp7leads to midfacial hypoplasia, nasal airway obstruction and disordered breathing, modeling obstructive sleep apnea

Abstract

Pediatric obstructive sleep apnea (OSA), a relatively common sleep-related breathing disorder (SRBD) affecting approximately 1-5% of children, is often caused by anatomical obstruction and/or collapse of the nasal and/or pharyngeal airways. The resulting sleep disruption and intermittent hypoxia lead to various systemic morbidities. Predicting the development of OSA from craniofacial features alone is currently not possible and a controversy remains if upper airway obstruction facilitates reduced midfacial growth or vice-versa. Currently, there is no rodent model that recapitulates both the development of craniofacial abnormalities and upper airway obstruction to address these questions. Here, we describe that mice with a neural crest-specific deletion of Bmp7 (Bmp7ncko) present with shorter, more acute angled cranial base, midfacial hypoplasia, nasal septum deviation, turbinate swelling and branching defects, and nasal airway obstruction. Interestingly, several of these craniofacial features develop after birth during periods of rapid midfacial growth and precede the development of an upper airway obstruction. We identified that in this rodent model, no single feature appeared to predict upper airway obstruction, but the sum of those features resulted in a reduced breathing frequency, apneas and overall reduced oxygen consumption. Metabolomics analysis of serum from peripheral blood identified increased levels of hydroxyproline, a metabolite upregulated under hypoxic conditions. As this model recapitulates many features observed in OSA, it offers unique opportunities for studying how upper airway obstruction affects breathing physiology and leads to systemic morbidities.

Nasal Septum Deviation as the Consequence of BMP-Controlled Changes to Cartilage Properties

“…Lineage tracing confirmed neural crest origin of septum chondrocytes and perichondrium ( n = 3/age) ( Figures 1G–I ). As previously shown ( Baddam et al, 2021a ), the nasal septum in BMP7 ncko mice becomes severely deviated by P30 ( Figures 1J–O ) ( n = 3/age/genotype) with the degree of deviation reaching between 10 and 35% ( Figure 1L ; p < 0.001) and variable in severity over time ( Figure 1O ). The nasal septum in the mouse grows rapidly between P7–P14 and P21–P30 but shows a significant reduction between P14 and P21 ( Vora et al, 2015 ; Baddam et al, 2021b ).…”

“…This study provides the first detailed characterization of the molecular and cellular etiology of NSD in a well-characterized model of midfacial hypoplasia associated with nasal airway obstruction ( Baddam et al, 2021a ). We uncovered that the deviated cartilage expressed several markers abundant in elastic cartilage and showed hallmarks commonly associated with osteoarthritic cartilage.…”

“…Why in some cases the septal hyaline cartilage would catastrophically fail has remained unclear. In the BMP7 ncko mouse, the initially straight septum gives way to a C-shaped kink, which is additionally associated with a growth defect resulting in midfacial hypoplasia ( Baddam et al, 2021a ). C or S-shaped deviations are commonly observed in neonates.…”

“…We recently described that mice with neural crest-specific deletion of BMP7 (BMP7 ncko ) develop midfacial hypoplasia and nasal airway obstruction ( Baddam et al, 2021a ). A hallmark of this model is the development of a significantly deviated nasal septum at a juvenile age that is associated with progression to abnormal breathing.…”

Developmental disorders Journal Meeting: a collaboration between Development and Disease Models & Mechanisms

“…The developing foetus is sensitive to signals, nutrients and pollutants from the environment, and these factors can combine with genetic risk factors to cause developmental disorders that vary in severity. This is especially true of neurocristopathies (Baddam et al, 2021;Wang et al, 2019), i.e. disorders caused by anomalies in the development of the neural crest, a transient embryonic migratory cell population in vertebrates.…”