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

Abstract

Lhx9 is a member of the LIM homeobox gene family. It is expressed during mammalian embryogenesis in the brain including the pineal gland. Deletion of Lhx9 results in sterility due to failure of gonadal development. The current study was initiated to investigate Lhx9 biology in the pineal gland. Lhx9 is highly expressed in the developing pineal gland of the rat with transcript abundance peaking early in development; transcript levels decrease postnatally to nearly undetectable levels in the adult, a temporal pattern that is generally similar to that reported for Lhx9 expression in other brain regions. Studies with C57BL/6J Lhx9−/− mutant mice revealed marked alterations in brain and pineal development. Specifically, the superficial pineal gland is hypoplastic, being reduced to a small cluster of pinealocytes surrounded by meningeal and vascular tissue. The deep pineal gland and the pineal stalk are also reduced in size. Although the brains of neonatal Lhx9−/− mutant mice appear normal, severe hydrocephalus develops in about 70 % of the Lhx9−/− mice at 5–8 weeks of age; these observations are the first to document that deletion of Lhx9 results in hydrocephalus and as such indicate that Lhx9 contributes to the maintenance of normal brain structure. Whereas hydrocephalus is absent in neonatal Lhx9−/−mutant mice, the neonatal pineal gland in these animals is hypoplastic. Accordingly, it appears that Lhx9 is essential for early development of the mammalian pineal gland and that this effect is not secondary to hydrocephalus.

A modulatory role of the Rax homeobox gene in mature pineal gland function: Investigating the photoneuroendocrine circadian system of a Rax conditional knockout mouse

“…; Yamazaki et al . ). The pinealocyte of the pineal gland and the retinal photoreceptor represent highly related cellular identities based on both morphological and molecular features (Collin ; Klein ; Bailey et al .…”

“…; Yamazaki et al . ). Homeobox genes regulate developmental processes; however, in the pineal gland, homeobox gene expression persists or is even restricted to postnatal stages (Rath et al .…”

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

“…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 . The homeobox genes Otx2 (orthodenticle homeobox 2) and Crx (cone‐rod homeobox) are highly expressed in the postnatal pineal gland of the rat …”

Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator

“…The homeobox transcription factors Pax6, Otx2 and Lhx9 are necessary for proper pineal gland formation [11–16]. Pax6 is considered one of the earliest phenotype determinants responsible for regulating pinealocyte specification and prenatal proliferation since the pineal gland fails to develop in the absence of functional Pax6.…”