The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation.
PACT is a double-stranded RNA-binding protein that also binds and activates the latent protein kinase, PKR, which plays a major role in cellular antiviral defense in mammals. For evaluating PACT's contribution to the innate immune system, Pact(-/-) mice have been generated; these mice exhibit notable developmental abnormalities including microtia, with craniofacial, ear, and hearing defects. Here we report that, in addition, Pact(-/-) mice had smaller body size and fertility defects, both of which were caused by defective pituitary functions. Pact(-/-) mice exhibited anterior pituitary lobe (AL) hypoplasia, which developed postnatally, when the second phase of pituitary expansion occurs. Among the 5 cell types in AL, the numbers of corticotrophs, gonadotrophs, and somatotrophs were equally decreased in Pact(-/-) mice with a greater impact on lactotrophs and a lesser impact on thyrotrophs. PACT mRNA and protein were highly expressed in the pituitary of wild-type (Wt) mice during the postnatal wave of AL proliferation, the same period in which the hypoplasia developed in Pact(-/-) mice. During this time, the pituitaries of Pact(-/-) mice did not exhibit significantly increased apoptosis compared with Wt mice but showed a decrease in cell proliferation. The inhibition of cell proliferation observed in vivo could be recapitulated in vitro in GH3 somato/lactotroph and LbetaT2 gonadotroph cell lines; knockdown of PACT expression with siRNA diminished the rate of proliferation of these cells. Our study revealed a physiologically significant role for PACT in cell proliferation and an essential role of a dsRNA-binding protein in mammalian pituitary expansion.
Peters
Gregory A
GA
Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Seachrist
Darcie D
DD
Keri
Ruth A
RA
Sen
Ganes C
GC
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D049628:Body Size / Q000235:genetics / Q000502:physiology; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D007246:Infertility / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008321:Mammary Glands, Animal / Q000002:abnormalities; D051379:Mice; D018345:Mice, Knockout; D010053:Ovary / Q000002:abnormalities; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
C119610:Prkra protein, mouse; C543819:Prkra protein, rat; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D013006:Growth Hormone