A role of the double-stranded RNA-binding protein PACT in mouse ear development and hearing

Abstract

To determine the physiological functions of the mammalian double-stranded RNA-binding protein PACT, the single-copy mouse Pact gene was disrupted and expression of the protein was completely ablated. The most notable phenotypes of the Pact ؊/؊ mouse were reduced size and severe microtia. As a result of the congenital abnormality of both outer and middle ears, these mice were hearing impaired. In situ hybridization revealed that PACT mRNA was expressed in specific regions of all three parts of the ear in adult and embryonic wild-type mice. Our study demonstrated an essential role of PACT in mammalian ear development and produced the first animal model for studying human microtia.gene disruption ͉ microtia ͉ antiviral ͉ innate immunity ͉ PKR

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

“…This implication of PACT in endocrine signaling is consistent with its reported role in postnatal anterior pituitary proliferation (25). Our findings add to the repertoire of functions of PACT, which includes the regulation of retinoic-acid-inducible gene 1 expression as part of the antiviral response (26), and ear development and hearing (27).…”

The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation

“…We previously established a crucial role of the dsRNA-binding protein PACT in proper development of craniofacial areas, the ears, and hearing (19). Here, we report additional and more pervasive developmental defects of Pact Ϫ/Ϫ mice and trace their origin to the central defect in development of the anterior lobe of the pituitary.…”

“…Previously, we generated Pact Ϫ/Ϫ mice and showed that these mice had developmental defects of the craniofacial area and the external/ internal ears, which led to hearing impairment (19). Adult mice had a severe reduction in the size of the outer ear and a large reduction in overall body size versus wild-type (Wt) mice (Fig.…”

“…To study the role of PACT in physiology, we previously generated Pact Ϫ/Ϫ mice in which PACT protein expression was completely ablated by disrupting the single copy mouse gene (19). These mice had craniofacial defects, congenital abnormalities of outer and middle ears, were hearing impaired, and serve as an animal model for studying human microtia.…”

NF-κB and the immune response

“…TLR2 also requires TIRAP to bridge MyD88 to the receptor; however it is believed that other MyD88-utilizing TLRs directly recruit MyD88. Recent reports suggest that the requirement for these intermediatory adapters is related to localization of the TLRs to certain domains in the plasma membrane Rowe et al, 2006). The N-terminal domain of MyD88 contains a death domain (DD) that recruits the DDcontaining serine/threonine kinase interleukin-1-associated kinase-4 (IRAK-4).…”