Defects in fetal mouth movement and pharyngeal patterning underlie cleft palate caused by retinoid deficiency.

Abstract

Cleft palate is a common birth defect. Etiologic mechanisms of palate cleft include defects in palate morphogenesis, mandibular growth, or spontaneous fetal mouth movement. Cleft palate linked to deficient fetal mouth movement has been demonstrated directly only in a single experimental model of loss of neurotransmission. Here, using retinoid deficient mouse embryos, we demonstrate directly for the first time that deficient fetal mouth movement and cleft palate occurs as a result of mis-patterned development of pharyngeal peripheral nerves and cartilages. Retinoid deficient embryos were generated by inactivation of retinol dehydrogenase 10 (Rdh10), which is critical for production of Retinoic Acid (RA) during embryogenesis. Using X-ray microtomography (microCT), in utero ultrasound, ex vivo culture, and tissue staining, we demonstrate that retinoid deficient mouse embryos lack fetal mouth movement owing to mis-patterning of pharyngeal cartilages and motor nerves. Findings from this study may indicate the earliest marker for diagnosing cleft palate. vii TABLE OF CONTENTS