Genetic analysis of FKBP8 and Kif3a in Sonic hedgehog signaling and neural patterning.

The embryonic neural tube is patterned through specification of distinct neural progenitor subtypes, each exhibiting a specific profile of transcription factor expression. This developmental event lays the groundwork for generation of the complex circuits within the central nervous system and it is governed by instructive signals from surrounding tissues. Among those signals, Sonic hedgehog (Shh) is a well characterized morphogen responsible for the specification of ventral cell fates along dorsal-ventral axis of the mammalian neural tube. How the quantitative information represented by distinct extracellular ligand concentrations is transduced accurately and precisely to specify unique cell fates remains unclear. In this work I have studied two mouse mutations which disrupt Shh-dependent neural patterning: a null mutation in Fkbp8 and an N-ethyl, N-nitrosourea (ENU)-induced recessive mutation, 2A. I analyzed chimeric embryos consisting of a mix of Fkbp8 mutant and wild-type cells and I used epistasis analysis to address the function of FKBP8 with respect to other Shh signaling components. My findings indicate that FKBP8 cell-autonomously antagonizes Shh signaling at a step downstream of Smoothened in a Gli2- and Kif3a-dependent manner. I have also found that FKBP8 plays an important secondary role in neural patterning by controlling the signaling environment through regulation of Bone morphogenetic protein (BMP) production. In addition, I found that the 2A mutation represent a novel allele of Kif3a , encoding a kinesin II subunit essential for ciliagenesis and Shh signaling. Whereas FKBP8 is essential to keep the Shh pathway appropriately repressed in the absence of Shh signals, Kif3a is important for activation of the pathway when neural progenitors have been exposed to these signals.