Double deletion of Panx1 and Panx3 affects skin and bone but not hearing

Abstract

Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knockout mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knockout mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages & Panx double KO mice had smaller litters and reduced body weight. & dKO skin had decreased epidermal and dermal area in neonatal mice. & Skull shape and size changed plus long bone length decreased in neonatal dKO mice. & dKO had no hearing loss and were slightly protected against noise-induced damage.

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca2+ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

“…Although pannexin 1 channels 71 are thought to mediate ATP release in other cellular systems, [76][77][78][79][80][81] the function of cochlear pannexins remains obscure. 34,[82][83][84] Prior work with the Panx1 −/− strain used here confirmed (i) successful ablation of Panx1 both in the cochlea and in the brain; (ii) normal hearing sensitivity, normal function of the outer hair cell-based "cochlear amplifier" and absence of cochlear nerve defects; (iii) normal expression of inner ear connexins and gap junction communication in the organ of Corti. 34 These published results and the data presented here together rule out that pannexin 1 channels contribute to the purinergic signaling that underlies Ca 2+ wave propagation in the developing cochlea.…”

ATP amplifies NADPH-dependent and -independent neutrophil extracellular trap formation

“…2B) levels. To exclude compensatory upregulation of other pannexin family members in Panx1 −/− BMDNs 22 , we verified for Panx2 and Panx3 transcripts, which were not detected in both WT and Panx1 −/− BMDNs (Fig. 4B).…”

Pannexin 3 regulates skin development via Epiprofin

“…6). Thus, other gap junction proteins in skin may help to maintain the metabolism of Panx3 −/− skin 43,44 .…”