The interactions between cdx transcription factors and the retinoic acid signaling pathway in regulating the regionalization of the posterior neural plate.

摘要

In vertebrates, the central nervous system (CNS) originates from a uniform neural tube that becomes patterned along the anterior-posterior (AP) axis to establish the four embryonic structures of the CNS, which are the forebrain, midbrain, hindbrain and spinal cord. The structures of the hindbrain and spinal cord share common characteristics not found in the forebrain and midbrain. Specifically, the hindbrain and the spinal cord both derive from the posterior neural plate and they both share expression of hox genes. However, despite these similarities the hindbrain and spinal cord undergo different developmental mechanisms where the hindbrain becomes transiently segmented into seven compartments while the spinal cord remains unsegmented. The underlying mechanisms that direct the posterior neural plate to form these two diverse structures remain unclear. We have previously shown that Cdx transcription factors are important regulators of spinal cord development where loss of Cdx leads to the replacement of the spinal cord with a mirror image duplicated posterior hindbrain. Although Cdx transcription factors have been shown to be required for spinal cord development, how it directs spinal cord development remains unexplored. To address this question we performed a microarray analysis by comparing the gene expression profile of wild-type and Cdx deficient embryos to identify downstream target genes of Cdx. Our microarray analysis and subsequent in-situ hybridization screen identify both hox genes and non-hox genes under the regulation of Cdx. Further functional studies on cellular retinoic acid binding protein 2a (Crabp2a), a molecule involved in the retinoic acid (RA) signaling pathway and a candidate gene from our microarray, show that Cdx interacts with the RA signaling pathway through regulation of crabp2a expression in the spinal cord. We also show that this regulatory interaction is involved in directing neural differentiation in the spinal cord. Furthermore, we show that Cdx also regulates another component of the RA signaling pathway, cyp26a1, to partition the posterior neural plate and to establish the AP-position of the hindbrain—spinal cord transition. From our findings, we propose that one mechanism in which Cdx regulates spinal cord development is through the modulation of the RA signaling pathway.