Identification of Eya3 and TAC1 as Long-Day Signals in the Sheep Pituitary

Abstract

Summary Seasonally breeding mammals such as sheep use photoperiod, encoded by the nocturnal secretion of the pineal hormone melatonin, as a critical cue to drive hormone rhythms and synchronise reproduction to the most optimal time of year [1, 2]. Melatonin acts directly on the pars tuberalis (PT) of the pituitary, regulating expression of thyrotropin (TSH) which then relays messages back to the hypothalamus to control reproductive circuits [3, 4]. In addition, a second local intra-pituitary circuit controls seasonal prolactin (PRL) release via a currently uncharacterised low molecular weight peptide(s) termed tuberalin(s) of PT origin [5–7]. Studies in birds identified the transcription factor Eya3 as the first molecular response activated by long photoperiods (LP) [8]. Using arrays and in situ hybridization studies, we show Eya3 as the strongest LP activated gene in sheep, revealing a common photoperiodic molecular response in birds and mammals. We also identified TAC1 (encoding the tachykinins Substance P and Neurokinin A; NKA) to be strongly activated by LP within the sheep PT. We show that these PRL secretagogues act on primary pituitary cells, and are thus candidates for the elusive PT-expressed “tuberalin” seasonal hormone regulator.

Encoding and Decoding Photoperiod in the Mammalian Pars Tuberalis

“…Both have the correct molecular weight for proposed tuberalins and their expression have previously been characterised in the PT [74]. The expression of the TAC1 gene encoding these peptides is progressively upregulated in the sheep PT following LP exposure [75], which parallels the progressive rise in PRL secretion. Intriguingly, the expression of the neurokinin receptors (NK1,2 and 3R) in the sheep PD is not observed in PRL expressing cells (lactotrophs), suggesting the involvement of indirect pathways perhaps via gonadotrophs or folliculo-stellate cells (FCS), as both of them express neurokinin receptors.…”

“…Recent studies, using cDNA microarrays in PT from sheep culled after 8 weeks of SP exposure or after one day of LP exposure, have identified Eya3 as a LP-induced gene, activated immediately after switching to LP exposure [75]. Eya3 is a transcription factor with multiple functions, the best described being its role in photoreceptor differentiation, suggesting that an ancient photoreceptor developmental pathway may be used in the PT to track the duration of the light/dark phase.…”

“…The transcriptional activation of specific set of genes, such as clock genes, at dusk and at dawn provides a local indication of the photoperiod [94]. The expression of Eya3 in LP is thought to be a major switch which drives an LP response among which is the activation of β TSH [75,102,103]. …”

When our body clocks run late: does it make us depressed?

“…This photoperiodic theory is based on the observation that the nocturnal elevation of the hormone melatonin has its offset about dawn, but this offset is delayed in the long nights of winter at high latitudes, in some conditions of delayed sleep phase or long sleep, and specifically in depression. Late melatonin offset suppresses expression of TSHB in pars tuberalis, resulting in less T3 synthesis in the hypothalamic third ventricle region and disturbed secretion of several pituitary hormones (15,16). Early morning bright light treatment, by suppressing melatonin and by correcting phase delays, makes the melatonin offset earlier.…”

Cells Co-Expressing Luteinising Hormone and Thyroid-Stimulating Hormone Are Present in the Ovine Pituitary Pars Distalis but Not the Pars Tuberalis: Implications for the Control of Endogenous Circannual Rhythms of Prolactin

“…For example, PRL-releasing factors of varying molecular weight (1-72 kDa) are released into PT-conditioned medium and modulate lactotroph activity in a photoperiod-dependent manner [6,7,38]. Moreover, the tachykinins, substance P and neurokinin A, are expressed in the PT [39] from where they stimulate PRL release [40,41], and the gene encoding their production, TAC1 , is upregulated during long days [41]. It is possible that the aforementioned photoperiod-induced changes in TSHB mRNA reflect a component of a wide-range response to the MEL signal that ultimately results in dynamic changes in the PRL-responsive PT gonadotroph, which in turn will convey the message to the PD lactotrophs.…”