Neural Crest-Specific Loss of Prkar1a Causes Perinatal Lethality Resulting from Defects in Intramembranous Ossification

Abstract

The cranial neural crest (CNC) undergoes complex molecular and morphological changes during embryogenesis in order to form the vertebrate skull, and nearly three quarters of all birth defects result from defects in craniofacial development. The molecular events leading to CNC differentiation have been extensively studied; however, the role of the cAMP-dependent protein kinase [protein kinase A (PKA)] during craniofacial development has only been described in palate formation. Here, we provide evidence that strict PKA regulation in postmigratory CNC cells is essential during craniofacial bone development. Selective inactivation of Prkar1a, a regulatory subunit of the PKA holoenzyme, in the CNC results in perinatal lethality caused by dysmorphic craniofacial development and subsequent asphyxiation. Additionally, aberrant differentiation of CNC mesenchymal cells results in anomalous intramembranous ossification characterized by formation of cartilaginous islands in some areas and osteolysis of bony trabeculae with fibrous connective tissue stabilization in others. Genetic interaction studies revealed that genetic reduction of the PKA catalytic subunit C(alpha) was able to rescue the phenotype, whereas reduction in Cbeta had no effect. Overall, these observations provide evidence of the essential role of proper regulation of PKA during the ossification of the bones of the skull. This knowledge may have implications for the understanding and treatment of craniofacial birth defects.

Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer

“…This data is consistent with our previously published work which suggests PKA is involved in differentiation and development in a number of cAMP responsive tissues (Jones et al, 2010; Nadella et al, 2008; Yin et al, 2008a). However, genes associated with thyrocyte terminal differentiation including, Thyroid Peroxidase , Thyroglobulin , and the Sodium-Iodide Symporter were all expressed at normal or even higher levels than WT in the R1a-TpoKO tumors (Supplementary Table 4).…”

Identification of circular RNA‐associated competing endogenous RNA network in the development of cleft palate

“…PRKAR1α encodes the cAMPdependent protein kinase (protein kinase A [PKA]) regulatory subunit type Ια and regulates neural crest development, migration, and differentiation during 45 The cranial neural crest cell originates in the ectodermal-neuroectodermal ridges of the cephalic neural folds, which subsequently undergo EMT and differentiate into most of the craniofacial structural components including the bones, nerves, connective tissue, and dentins in the embryonic stage. 46 Jones et al 47 reported that aberrant differentiation of neural crest mesenchymal cells resulted in CP. cAMP levels increase in the palate mesenchyme immediately before fusion of the palatal shelves, which is accompanied by increased PKA activation.…”

cAMP/PKA signaling defects in tumors: Genetics and tissue-specific pluripotential cell-derived lesions in human and mouse

“…Several tissue-specific KOs (neural crest, heart, pituitary, adrenal, thyroid) from the original Prkar1a loxp/lop line have now either been published or are near completion (Jones et al, 2010b; Yin et al, 2008a; Sahut-Barnola et al, 2010; Jones et al, 2010a; Yin et al, 2008b, 2008c). …”

“…However, it appears that β-catenin activation in R1α–deficient cells is an event preceded by yet unknown molecular abnormalities that take place within the still benign and R1α-haploinsufficient tissues in the early stages of tumor formation (Almeida et al, 2011b; Almeida et al 2012). The discovery that neural crest (Jones et al, 2010b), heart (Yin et al, 2008a), adrenal (Sahut-Barnola et al, 2010)-specific knockouts (KO) of R1α or other mice with R1α defects (Almeida et al, 2010; Tsang et al, 2010; Kirschner, et al, 2005; Griffin et al, 2004; Griffin et al, 2004; Pavel et al, 2008; Molyneux et al, 2010; Jones et al, 2010a), develop lesions caused by proliferation of stem cell-like TSPCs in adult tissues, such as the adult skeleton (Tsang et al, 2010; Pavel et al, 2008) was an important one that further supported the possible role of Wnt -signaling in R1α defects, since Wnt -signaling is critical for the maintenance and/or proliferation of pluripotential cells.…”