Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

Abstract

Previous in vitro studies have indicated multiple and varied roles of Pinin (PNN); however, its in vivo role has remained unclear. Here, we report generation of null, hypomorphic, and conditional Pnn alleles in mice. We found that insertion of neomycin-resistance cassette into intron 8 of Pnn resulted in knockdown of Pnn, which allowed Pnn hypomorphic embryos to pass peri-implantation lethality. These mice are lethal at perinatal stages and exhibit defects in the cardiac outflow tract, palate, dorsal dermis, and axial skeleton. Since Wnt/␤-catenin signaling has been shown to play pivotal roles in development of all tissues affected by Pnn hypomorphism, we speculated that Pnn may affect Wnt/␤-catenin signaling. Supporting this view, we demonstrate abnormal activities of Tcf/Lef transcription factors, and alterations in ␤-catenin level in multiple Pnn hypomorphic tissues. Taken together, the data suggest that Pnn plays important roles during mouse development through its involvement in regulation of Tcf/Lef activity. Developmental Dynamics 236: 2147-2158, 2007.

Corepressor CtBP and Nuclear Speckle Protein Pnn/DRS Differentially Modulate Transcription and Splicing of the E-Cadherin Gene

“…28,2008 CtBP (21). Splicing assays were performed using RT-PCR, where unspliced message was detected using primers against E-cadherin intron 2, whereas total spliced E-cadherin message was detected using primers spanning the region between exons 4 and 8 (Fig.…”

Loss of Pnn expression results in mouse early embryonic lethality and cellular apoptosis through SRSF1-mediated alternative expression of Bcl-xS and ICA**

“…Targeted disruption of Sfrs10 (Mende et al, 2010), SRp20, SRSF2 (also known as SC35), and SRSF1 (also known as ASF/ SF2) resulted in early embryonic lethality (Moroy and Heyd, 2007). Recently, using a tissue-specific mouse model with deletion of exons 3-8 in pnn gene, investigators showed that Pnn plays important roles in development of the heart, cornea, and intestine (Joo et al, 2007;Joo et al, 2010a;Joo et al, 2010b). Although all of these loss-of-function mouse models demonstrated that SR proteins are important for embryonic development, the underlying mechanism relating loss of SR protein expression to embryonic lethality or cellular apoptosis has not been clarified.…”

Dissection of the role of Pinin in the development of zebrafish posterior pharyngeal cartilages

“…They are then guided to their destinations and differentiate into mature structures. Hypomorphic reduction of pnn resulted in a wide range of developmental defects in mice (Joo et al 2007). Disorganized dorsal dermis devoid of brown adipose tissue, and malformation of axial skeleton in pnn hypomorphic mice suggested that pnn is important for the development of these somite derivatives.…”

“…Disorganized dorsal dermis devoid of brown adipose tissue, and malformation of axial skeleton in pnn hypomorphic mice suggested that pnn is important for the development of these somite derivatives. In addition, defects in the cleft palate, cardiac outflow tract and craniofacial skeleton indicated that pnn also has an essential role in neural crest development (Joo et al 2007).…”

“…Pinin (pnn) is a desmosome and nuclear-associated moonlighting phosphoprotein (Ouyang 1999) that is involved in cell-cell adhesion, tumor suppression, pre-mRNA splicing, transcriptional regulation, and mouse embryogenesis (Shi et al 2001;Zimowska et al 2003;Alpatov et al 2004;Joo et al 2005Joo et al , 2007. Previous in vitro studies have demonstrated that overexpression of pnn results in enhancement of intercellular adhesion and a decrease in cell motility and proliferation (Ouyang and Sugrue 1996;Shi et al 2000a), while downregulation of pnn by shRNA caused cells to become less adherent and more migratory (Joo et al 2005).…”