Endocrine - Pineal Development

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Developing pineal gland
Adult pineal body
Pineal gland position

The pineal gland (epiphysis cerebri) has an important role in the sleep/wake daily cycle (circadian), high melatonin plasma levels at nighttime and very low levels at daytime, and reproductive development. The gland is thought to evolutionarily to have been positioned as to be exposed to light, and hence remains a regulator of cyclic rhythms associated with day/night and day length. The pineal hormone (melatonin) has targets both in the nervous system and in many different peripheral tissues.

The embryo and fetus pineal does not produce significant amounts of melatonin, though the maternal pineal gland produces melatonin in the normal circadian fashion and this melatonin can cross both the placenta and blood-brain barrier. In other species, maternal melatonin crosses the placenta into fetal circulation and may provide photoperiodic information during fetal development that influences later postnatal circadian (daily day/night) and seasonal (day length) rhythms. The pineals of non-mammalian vertebrates are photoreceptive, whereas those of mammals do not normally respond to directly light.

Postnatally in humans, the melatonin levels in premature infants is lower and delayed, but not different when calculated from conception date. Other factors such as preeclampsia, growth restriction, and nursery lighting can cause altered rhythm development. The same study has also shown that full-term infants born at home and full-term twins born in the hospital had significantly lower metabolite excretion levels than hospital-born singleton infants at the same ages despite similar body weights.[1]


  • part of epithalmus - neurons, glia and pinealocytes
  • pinealocytes secrete melatonin - cyclic nature of activity, melatonin lowest during daylight
    • inhibit hypothalamic secretion of GnRH until puberty, pineal gland then rapidly regresses.
  • other activities - possibly gamete maturation, antioxidant effect, protect neurons?

Note that there are many clinical studies investigating the possible role of melatonin in diverse health areas, from oxygen starvation at birth through to neural effects in old age.

Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | Pineal | Hypothalamus‎ | Pituitary | Thyroid | Parathyroid | Thymus‎ | Pancreas‎ | Adrenal‎ | Gonad‎ | Placenta‎ | Other Tissues | Stage 22 | Abnormalities | Hormones | Category:Endocrine
Historic Embryology - Endocrine  
1903 Islets of Langerhans | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Hypophyseal fossa | 1935 Hypophysis | 1937 Pineal | 1938 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal
Lecture - Endocrine Development | Lecture - Head Development | 1937 Human Pineal | Category:Pineal

Some Recent Findings

Mouse pineal E15 to E21 neuroepithelium
Mouse pineal E15 to E21 neuroepithelium[2]
  • Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator[2] "The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. ...The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers."
  • The Lhx9 homeobox gene controls pineal gland development and prevents postnatal hydrocephalus[3] "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 hypo plastic."
  • Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology[4] "A number of conclusions naturally evolve from the data summarized in this review: (i) melatonin, of both pineal and placental origin, has essential functions in fetal maturation and placenta/uterine homeostasis; (ii) circadian clock genes, which are components of all cells including those in the peripheral reproductive organs, have important roles in reproductive and organismal (fetal and maternal) physiology; (iii) due to the potent antioxidant actions of melatonin, coupled with its virtual absence of toxicity, this indoleamine may have utility in the treatment of pre-eclampsia, intrauterine growth restriction, placental and fetal ischemia/reperfusion, etc. (iv) the propensity for parturition to occur at night may relate to the synergism between the nocturnal increase in melatonin and oxytocin."
  • Melatonin as a central molecule connecting neural development and calcium signaling[5] "Melatonin (MEL) is a neuroendocrine hormone secreted by the pineal gland in association with the suprachiasmatic nucleus and peripheral tissues. MEL has been observed to play a critical role in the reproductive process and in the fetomaternal interface. Extrapineal synthesis has been reported in mammalian models during pregnancy, especially by the placenta tissue."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Pineal Embryology

Jun Song, Sai-Jun Ma, Jian-Hua Luo, Hui Zhang, Ri-Xiong Wang, Hui Liu, Li Li, Zhi-Guang Zhang, Rui-Xiang Zhou Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway. Oncol. Rep.: 2018; PubMed 29484412

Irfan Susko, Selma Alicelebic, Esad Cosovic, Maida Sahinovic, Dina Kapic, Samra Custovic, Visnja Muzika Gender-related Histological Changes in the Thymus Gland After Pinealectomy and Short-term Melatonin Treatment in Rats. Med Arch: 2017, 71(6);385-390 PubMed 29416196

Malena L Mul Fedele, Maria D Galiana, Diego A Golombek, Estela M Muñoz, Santiago A Plano Alterations in Metabolism and Diurnal Rhythms following Bilateral Surgical Removal of the Superior Cervical Ganglia in Rats. Front Endocrinol (Lausanne): 2017, 8;370 PubMed 29375476

Ágnes Csáki, Viktória Vereczki, Ákos Lukáts, Zsolt Boldogkői, Anna Sebestyén, Zita Puskár, Katalin Köves Ontogenesis of the pinealo-retinal neuronal connection in albino rats. Neurosci. Lett.: 2017; PubMed 29217260

Bianka Bojková, Karol Kajo, Terézia Kisková, Peter Kubatka, Pavol Žúbor, Peter Solár, Martin Péč, Marián Adamkov Metformin and melatonin inhibit DMBA-induced mammary tumorigenesis in rats fed a high-fat diet. Anticancer Drugs: 2017; PubMed 29200002

Development Overview

  • Neuroectoderm - prosenecephalon then diencephalon
  • caudal roof, median diverticulum, epiphysis
  • Initially a hollow diverticulum, cell proliferation to solid, pinealocytes (neuroglia), cone-shaped gland innervated by epithalamus

Epithalamus consists of the pineal gland and habenular nuclei

Fetal Pineal Anatomy[6]

Superior (dorsal) view of the diencephalic-mesencephalic area of a 3.5-month-old human fetus.

The third ventricle (3 ventr) without pial covering is seen to the right in the micrograph.

The small pineal gland is a small protuberance (arrow) and merging via the broad stalk with the habenula (Ha). Sup col.: superior colliculus.

Bar = 2 mm.

Fetal pineal gland 01.jpg


Melatonin molecular structure
  • Melatonin is synthesized from the amino acid tryptophan within the pinealocytes.
    • Serotonin is first acetylated by aryl alkylamine N-acetyltransferase (AA-NAT), then converted to melatonin by acetyl serotonin methyl transferase (ASMT also known as hydroxyindole O-methyltransferase or HIOMT).
  • Melatonin release is stimulated by darkness and inhibited by light and is said to have neurological "chronobiotic" properties for resynchronization of sleep and circadian rhythms disturbances. In the periphery, melatonin is also involved in the regulation of several complex cycles: seasonal reproduction, body weight and energy balance.
  • Melatonin levels can be monitored by urinary excretion of the melatonin metabolite 6-sulfatoxymelatonin (aMT.6S).

Melatonin Receptors

The hormone melatonin acts through receptors (high affinity G protein-coupled) embedded in the cell membrane. Three different receptor subtypes have been identified in mammals: MT1 (Mel 1a) and MT2 (Mel 1b) and a putative binding site called MT3.

  • MT1 - expressed in humans in the pars tuberalis of the pituitary gland and the suprachiasmatic nuclei of the hypothalamus.
  • MT2 - expressed in the retina.
  • MT3 - expressed in many non-mammalian vertebrates in a range of brain areas.
Links: Image - melatonergic receptors coupled via Gαi


The gland is connected to the hypothalamus suprachiasmatic nucleus (SCN) central rhythm generator through a multi-synaptic pathway.

Nerve fibers innervating the mammalian pineal gland originate from perikarya located in the sympathetic superior cervical ganglion, the parasympathetic sphenopalatine and otic ganglia, as well as by nerve fibers originating in the central nervous system.[7]

  • sympathetic nerves - contain norepinephrine and neuropeptide Y as neurotransmitters
  • parasympathetic nerves - contain vasoactive intestinal peptide and peptide histidine isoleucine
  • trigeminal ganglion - containing substance P, calcitonin gene-related peptide, and pituitary adenylate cyclase-activating peptide

Molecular Development

Mouse pineal E15 to E21 neuroepithelium 01.jpg

Mouse pineal gland (E15 to E21)

The pineal gland develops from neuroepithelial cells that express the transcription factor Pax6 and the intermediate filament vimentin.

Panels display confocal microscopy of immunolabeled sagittal sections of rat pineal gland (PG) from embryonic day (E) 15 to E21.

  • A1-G1 show expression of Pax6 (green) and vimentin (VIM, red) in pineal precursor cells at low magnification.
  • A2-G2 display the same structures at higher magnification.
  • A3-G3 and A4-G4 show Pax6 and vimentin expression for each stage of development, respectively.

Pineal organogenesis begins around E15 as an evagination of the neuroepithelium in the dorsal diencephalon that is densely populated by Pax6-expressing cells (green). The developing PG becomes a tubular extension at E16. The orientation of Pax6/VIM+ cells is radial at these stages. At E17 the pineal neuroepithelium begins to fold and fuses at the midline. After fusion of the neuroepithelium, double immunolabeled rosette-like structures are visible in the E18-E21 developing PG. At E21 the PG has developed into a recognizable globular structure. (A1-G1) 20x; scale bar: 75 μm. (A2-G4) 60x; scale bar: 25 μm. PC, posterior commissure. SCO, subcommissural organ. 3v, third ventricle.

  • Nodal - zebrafish required for dorsal convergence of pineal precursors.[8]
  • Pax6 - rat pineal gland from E16, peak expression around E18.[9]
  • Fgf8a - zebrafish epithalamus acts permissively to promote parapineal fate.[10]
  • DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is involved in the retinal pathway transmitting photic information that resets the circadian clock.

Links: Molecular Development


  • Pineal Hypoplasia associated with retinal disease.
  • Pineal Tumours in children are associated with abnormal puberty development.


Adult Pineal (sheep)

Adult Histology

  • Astrocytes - small dark nuclei
  • Pinealocytes - most nuclei present, larger lighter and round nuclei surrounded by a broad rim of light cytoplasm
  • Endothelial cells - nuclei in association with the vessels and capillaries traversing the tissue.
  • Cytoplasmic processes - "stringy" appearance from both pinealocytes and astrocytes

Links: large histology image



Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic Textbook" and "Historic Embryology" appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms and interpretations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Cooper, ERA. The Human Pineal Gland and Pineal Cysts (1932)

Cooper1932-fig01.jpg Cooper1932-fig02.jpg
Fig. 1. Sagittal midline section through head of 25 mm. embryo. x 8. A, anlage of pineal gland in the form of a backward hollowextension. B, anlage of posterior commissure. C, third ventricle. D, pituitary body. Fig. 2. Sagittal section through head of 35 mm. embryo, not quite median. x 10. A, anterior anlage of pineal. B, posterior anlage with divertioulum pineale. C, posterior commisaure. D, third ventricle. E, pituitary body.


  1. D J Kennaway, F C Goble, G E Stamp Factors influencing the development of melatonin rhythmicity in humans. J. Clin. Endocrinol. Metab.: 1996, 81(4);1525-32 PubMed 8636362
  2. 2.0 2.1 María P Ibañez Rodriguez, Stephen C Noctor, Estela M Muñoz Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator. PLoS ONE: 2016, 11(11);e0167063 PubMed 27861587
  3. Fumiyoshi Yamazaki, Morten Møller, Cong Fu, Samuel J Clokie, Artem Zykovich, Steven L Coon, David C Klein, Martin F Rath The Lhx9 homeobox gene controls pineal gland development and prevents postnatal hydrocephalus. Brain Struct Funct: 2015, 220(3);1497-509 PubMed 24647753
  4. Russel J Reiter, Dun Xian Tan, Ahmet Korkmaz, Sergio A Rosales-Corral Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Hum. Reprod. Update: 2013, 20(2);293-307 PubMed 24132226
  5. Joice de Faria Poloni, Bruno César Feltes, Diego Bonatto Melatonin as a central molecule connecting neural development and calcium signaling. Funct. Integr. Genomics: 2011, 11(3);383-8 PubMed 21465271
  6. Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu Neuropeptide Y in the adult and fetal human pineal gland. Biomed Res Int: 2014, 2014;868567 PubMed 24757681 | PMC3976832 | Biomed Res Int.
  7. Morten Møller, Florian M M Baeres The anatomy and innervation of the mammalian pineal gland. Cell Tissue Res.: 2002, 309(1);139-50 PubMed 12111544
  8. Allisan Aquilina-Beck, Kristine Ilagan, Qin Liu, Jennifer O Liang Nodal signaling is required for closure of the anterior neural tube in zebrafish. BMC Dev. Biol.: 2007, 7;126 PubMed 17996054
  9. Martin F Rath, Kristian Rohde, David C Klein, Morten Møller Homeobox genes in the rodent pineal gland: roles in development and phenotype maintenance. Neurochem. Res.: 2013, 38(6);1100-12 PubMed 23076630
  10. Joshua A Clanton, Kyle D Hope, Joshua T Gamse Fgf signaling governs cell fate in the zebrafish pineal complex. Development: 2013, 140(2);323-32 PubMed 23250206

Online Textbooks



Dietmar Weinert Ontogenetic development of the mammalian circadian system. Chronobiol. Int.: 2005, 22(2);179-205 PubMed 16021838

M Mila Macchi, Jeffrey N Bruce Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol: 2004, 25(3-4);177-95 PubMed 15589268

J Barrenetxe, P Delagrange, J A Martínez Physiological and metabolic functions of melatonin. J. Physiol. Biochem.: 2004, 60(1);61-72 PubMed 15352385

Peter Ekström, Hilmar Meissl Evolution of photosensory pineal organs in new light: the fate of neuroendocrine photoreceptors. Philos. Trans. R. Soc. Lond., B, Biol. Sci.: 2003, 358(1438);1679-700 PubMed 14561326

L Thomas, J E Drew, D R Abramovich, L M Williams The role of melatonin in the human fetus (review). Int. J. Mol. Med.: 1998, 1(3);539-43 PubMed 9852259


Bo Sun, Dan Wang, Yuchun Tang, Lingzhong Fan, Xiangtao Lin, Taifei Yu, Hengtao Qi, Zhenping Li, Shuwei Liu The pineal volume: a three-dimensional volumetric study in healthy young adults using 3.0 T MR data. Int. J. Dev. Neurosci.: 2009, 27(7);655-60 PubMed 19665543

S M Al-Hussain The pinealocytes of the human pineal gland: A light and electron microscopic study. Folia Morphol. (Warsz): 2006, 65(3);181-7 PubMed 16988913

Shin Saito, Tetsuya Tachibana, Yang-Ho Choi, D Michael Denbow, Mitsuhiro Furuse ICV melatonin reduces acute stress responses in neonatal chicks. Behav. Brain Res.: 2005, 165(2);197-203 PubMed 16182388

M Sumida, A J Barkovich, T H Newton Development of the pineal gland: measurement with MR. AJNR Am J Neuroradiol: 1996, 17(2);233-6 PubMed 8938291

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Cite this page: Hill, M.A. (2018, March 20) Embryology Endocrine - Pineal Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Endocrine_-_Pineal_Development

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