Neuroanatomical Analysis of a Conditional Knockin Mutant PHOX2B Mouse Model

Abstract

BackgroundCentral Congenital Hypoventilation Syndrome (CCHS) is a rare disorder characterized by autonomic dysfunction, including abnormal respiration. Symptoms of CCHS include the inability to establish a regular respiratory rhythm, inadequate responses to hypoxemia and hypercapnia, heart rate abnormalities, and impaired bowel function. Mutations in paired‐like homeobox 2b (PHOX2B) are known to be causative for CCHS. We previously demonstrated that mice harboring an eight‐nucleotide deletion in PHOX2B (d8‐PHOX2B) displayed diffuse hindbrain pathology and perinatal lethality due to lack of spontaneous respiration. In this study, we are further exploring which brainstem circuits are required at birth for proper respiratory function and whether specific circuits are lost or insufficiently matured in mice expressing d8‐PHOX2B.MethodsWe are crossing several Cre driver mice with d8‐PHOX2B mice to selectively express d8‐PHOX2B in hindbrain neural nuclei known to be affected by mutant PHOX2B expression. Histological examination of brainstems from these mice along with unbiased quantification will allow us to determine how the morphology and number of cells within these neural populations is altered.Preliminary resultsAtoh1‐cre; d8‐PHOX2B mice were generated and assessed for perinatal viability, as Atoh1 is a transcription factor known to be involved in the development of medullary respiratory centers. At birth Atoh1‐cre; d8‐PHOX2B pups appeared healthy and displayed spontaneous respiration. Histological examination of hindbrains from these pups revealed no neuropathology, with evident intact locus coeruleus, facial nucleus, and retrotrapezoid nucleus. These preliminary results suggest that the expression of Phox2b in the Atoh1 lineage is not required for normal hindbrain development and respiration at birth.Support or Funding Information1R01HL132355‐01A1