Neural crest-specific deletion of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction, and disordered breathing modelling Obstructive Sleep Apnea

Pranidhi Baddam; Vivian Biancardi; Daniela M Roth; Farah Eaton; Claudine Thereza-Bussolaro; Rupasri Mandal; David S Wishart; Amy Barr; Joanna MacLean; Carlos Flores-Mir; Silvia Pagliardini; Daniel Graf

doi:10.1242/dmm.047738

Neural crest-specific deletion of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction, and disordered breathing modelling Obstructive Sleep Apnea

Dis Model Mech. 2021 Jan 11;14(2):dmm047738. doi: 10.1242/dmm.047738. Online ahead of print.

Authors

Pranidhi Baddam¹, Vivian Biancardi^{2

3}, Daniela M Roth^{1

3}, Farah Eaton¹, Claudine Thereza-Bussolaro^{1

4}, Rupasri Mandal⁵, David S Wishart⁵, Amy Barr⁶, Joanna MacLean^{7

8}, Carlos Flores-Mir¹, Silvia Pagliardini², Daniel Graf^{9

10}

Affiliations

¹ School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
² Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
³ Equal contributions.
⁴ Department of Dentistry, Hospital dos Pinheiros, UNIFASIPE, Sinop, Mato Grosso, Brazil.
⁵ The Metabolomics Innovation Centre, Department of Biological Sciences, Faculty of Science, University of Alberta, Edmonton, AB, Canada.
⁶ Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
⁷ Department of Pediatrics and the Women & Children's Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta.
⁸ Stollery Children's Hospital; Edmonton, AB, Canada.
⁹ School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada dgraf@ualberta.ca.
¹⁰ Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

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 (Bmp7^ncko) 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.

Keywords: Airway obstruction; Apneas; Bone Morphogenetic Protein 7; Midfacial hypoplasia; Nasal septum deviation; Sleep related breathing disorders; Turbinate hypertrophy.