Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube.

Protein kinase A is an evolutionarily conserved negative regulator of the hedgehog (Hh) signal transduction pathway. is known to be required for the proteolytic processing event that generates the repressor forms of the Ci and Gli transcription factors that keep target genes off in the absence of Hh. Here, we show that complete loss of duanyu1529 activity in the mouse leads to midgestation lethality and a completely ventralized neural tube, demonstrating that duanyu1529 is as strong a negative regulator of the sonic hedgehog (Shh) pathway as patched 1 (Ptch1) or suppressor of fused (Sufu). Genetic analysis shows that although duanyu1529 is important for production of the repressor form of Gli3, the principal function of duanyu1529 in the Shh pathway in neural development is to restrain activation of Gli2. Activation of the Hh pathway in duanyu1529 mutants depends on cilia, and the catalytic and regulatory subunits of duanyu1529 are localized to a compartment at the base of the primary cilia, just proximal to the basal body. The data show that duanyu1529 does not affect cilia length or trafficking of smoothened (Smo) in the cilium. Instead, we find that there is a significant increase in the level of Gli2 at the tips of cilia of cells. The data suggest a model in which duanyu1529 acts at the base of the cilium after Gli proteins have transited the primary cilium; in this model the sequential movement of Gli proteins between compartments in the cilium and at its base controls accessibility of Gli proteins to which determines the fates of Gli proteins and the activity of the Shh pathway.

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