Crx broadly modulates the pineal transcriptome

Abstract

Cone-rod homeobox (Crx) encodes Crx, a transcription factor expressed selectively in retinal photoreceptors and pinealocytes, the major cell type of the pineal gland. Here, the influence of Crx on the mammalian pineal gland was studied by light and electron microscopy and by use of microarray and qRTPCR technology, thereby extending previous studies on selected genes (Furukawa et al. 1999). Deletion of Crx was not found to alter pineal morphology, but was found to broadly modulate the mouse pineal transcriptome, characterized by a >2-fold downregulation of 543 genes and a >2-fold upregulation of 745 genes (p < 0.05). Of these, one of the most highly upregulated (18-fold) is Hoxc4, a member of the Hox gene family, members of which are known to control gene expression cascades. During a 24-hour period, a set of 51 genes exhibited differential day/night expression in pineal glands of wild-type animals; only eight of these were also day/night expressed in the Crx−/− pineal gland. However, in the Crx−/− pineal gland 41 genes exhibit differential night/day expression that is not seen in wild-type animals. These findings indicate that Crx broadly modulates the pineal transcriptome and also influences differential night/day gene expression in this tissue. Some effects of Crx deletion on the pineal transcriptome might be mediated by Hoxc4 upregulation.

Large-Scale Identification of Coregulated Enhancer Networks in the Adult Human Brain

“…This demonstrates that coregulated enhancers can be identified and grouped into specific networks using both single sample-enriched as well as multiple sample-enriched enhancer states as a viewpoint ( Figures 3E and 3F). Using this analysis for an enhancer selectively enriched in the pineal gland, we identified 334 enhancers that were enriched for the CRX transcription factor binding site, which is a master regulator of pineal specific gene expression patterns ( Figure S3) (Rovsing et al, 2011). Thus, our analysis of coregulated enhancer networks over a large number of brain regions allows us to substantially increase the resolution of enhancer analysis in heterogeneous tissue compared with the analysis of single data sets.…”

Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance

“…The pineal gland of the Crx knockout develops normally [85,88], suggesting that Crx , in contrast to the situation in the retina, is not essential for pineal gland development. However, double knockout studies suggest that the apparent integrity of the pineal gland is due to complementation by Otx2 [87].…”

“…5), as is the case in the retinal photoreceptor. Notably, CRX itself trans -activates and confers tissue-specific expression of a number of genes involved in phototransduction and melatonin synthesis in the pineal gland and retina [80,81,85,88–91] (see section 4). In both tissues, the developmental appearance of Crx transcripts immediately precedes that of melatonin- and vision-related gene products with clearly defined physiological roles (Fig.…”

The Lhx9 homeobox gene controls pineal gland development and prevents postnatal hydrocephalus

“…The pineal gland, a neuroendocrine organ converting photoperiodic information into the nocturnal hormonal signal of melatonin (Moller and Baeres 2002; Klein 2007), has been shown to express a number of homeobox genes both during development and postnatally (Rath et al 2013). Pineal homeobox genes include members of the orthodenticle (Otx) and paired box (Pax) families (Rath et al 2006, 2009); among these, Pax6 and Otx2 are known to be essential for pineal gland development (Nishida et al 2003; Estivill-Torrus et al 2001b), whereas the Otx-related cone–rod homeobox gene ( Crx ) exerts its function later in life by governing pineal-specific melatonin synthesis (Furukawa et al 1999; Rovsing et al 2011). …”