Abstract
We have studied the function of protein kinase A (PKA) during embryonic development using a PKA-deficient mouse that retains only one functional catalytic subunit allele, either Calpha or Cbeta, of PKA. The reduced PKA activity results in neural tube defects that are specifically localized posterior to the forelimb buds and lead to spina bifida. The affected neural tube has closed appropriately but exhibits an enlarged lumen and abnormal neuroepithelium. Decreased PKA activity causes dorsal expansion of Sonic hedgehog signal response in the thoracic to sacral regions correlating with the regions of morphological abnormalities. Other regions of the neural tube appear normal. The regional sensitivity to changes in PKA activity indicates that downstream signaling pathways differ along the anterior-posterior axis and suggests a functional role for PKA activation in neural tube development.
Highlights
Many studies have demonstrated roles for protein kinase A (PKA)1 in the regulation of postnatal physiology, but limited knowledge has been gained on the function of PKA in mammalian development
We have studied the function of protein kinase A (PKA) during embryonic development using a PKA-deficient mouse that retains only one functional catalytic subunit allele, either C␣ or C, of PKA
Decreasing PKA activity resulted in an increase in apoptotic cell death in the abnormal neuroepithelium and dorsal root ganglia, suggesting that PKA activity plays an anti-apoptotic role in the developing neural tube
Summary
Many studies have demonstrated roles for protein kinase A (PKA) in the regulation of postnatal physiology, but limited knowledge has been gained on the function of PKA in mammalian development. Manipulation of PKA activity in vertebrates has suggested that the negative regulation of the Sonic hedgehog (Shh) signaling pathway is conserved [5,6,7,8]. There are two catalytic (C␣ and C) and four regulatory (RI␣, RI, RII␣, and RII) subunit genes of PKA identified in mice [11]. One way to solve this problem is to use PKA knockout mice, and we have created null mutations in each of the four regulatory and two catalytic subunits of PKA expressed in the mouse. Decreasing PKA activity resulted in an increase in apoptotic cell death in the abnormal neuroepithelium and dorsal root ganglia, suggesting that PKA activity plays an anti-apoptotic role in the developing neural tube. All of the defects were observed in the posterior neural tube from the thoracic to sacral regions, whereas the cervical neural tube appeared normal, suggesting differential dependence on PKA activity along the anterior-posterior axis
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