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

Abstract

The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.

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

“…Normal pineal development requires a network of regulatory transcription factors, including a number of homeobox gene-encoded modulators, that have to be expressed in the developing pinealocyte in a timely coordinated manner (Rath et al 2013). In the current study, we examined the pineal biology of Lhx9 , a homeobox gene that has not previously been associated with pineal gland development.…”

“…As noted in the “Introduction”, pineal homeobox genes display different temporal patterns of expression (Rath et al 2013). Pax6 expression is restricted to prenatal stages, followed by Otx2, Crx and Rax (retina and anterior neural fold homeobox), which are expressed throughout development into adulthood, whereas Pax4 is restricted to postnatal stages (Fig.…”

“…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).…”

Homeobox Genes and Melatonin Synthesis: Regulatory Roles of the Cone-Rod Homeobox Transcription Factor in the Rodent Pineal Gland

“…Otx2 and Crx expression peak around birth [14], at which time Aanat expression is initiated [19]. The spatial and temporal correlation between peaks in expression of Otx2 and Crx and the start of Aanat expression supports that the OTX2 and CRX homeodomain transcription factors induce Aanat transcription [7]. E, embryonic day; P, postnatal day.…”

Homeobox genes in melatonin‐producing pinealocytes: Otx2 and Crx act to promote hormone synthesis in the mature rat pineal gland

“…While protein kinase A is widely expressed in different tissues, melatonin synthesis is restricted to the pineal gland and in nonprimate species the retinal photoreceptor. An increasing amount of evidence suggests that tissue‐specific melatonin synthesis is controlled by homeobox gene‐encoded transcription factors . Homeobox genes generally control developmental processes, but in the pineal gland, expression persists or is even restricted to postnatal stages .…”