Embryonic origin of temperament: notochord and early signaling

Main Article Content

samuel Ruesga https://orcid.org/0009-0000-3484-0460

Keywords

Temperament., Gastrulation, Notochord, Prenatal Epigenetic Programming

Abstract

 


Abstract


Background: It is proposed that the origin of temperament is rooted in events of the third week of gestation, when gastrulation and the notochord organize body axes and morphogenetic gradients, integrated through intracellular pathways with downstream effects on circuit architecture and locomotion.


Objective: To propose a theoretical mechanistic model that articulates how gastrulation, the notochord, and prenatal epigenetic programming could contribute—probabilistically rather than deterministically—to the origin of human temperament.


Material and methods: Original contribution of opinion/theoretical model, derived from an interdisciplinary narrative review. No experiments or quantitative meta-analyses were conducted; the aim is to articulate a hypothesis-generating mechanistic framework.


Results: A three-phase mechanistic flow is proposed: Phase 1, in which gastrulation and the notochord establish axes and gradients that could modulate the organization of ventral circuits and central pattern generators; Phase 2, in which prenatal epigenetic programming calibrates stress, immune, and affective axes; and Phase 3, in which these levels integrate into profiles of activity, exploration, reactivity, and inhibition, consistent with the distributed polygenic architecture described by personality genomics.


Conclusions: The notochord emerges as a plausible morphogenetic axis of temperament. Upon this embryonic scaffold, prenatal epigenetic programming may calibrate allostasis, stress reactivity, and affectivity, contributing to long-term temperamental variation. The model formulates falsifiable hypotheses and suggests translational priorities in perinatal prevention, multimodal biomarkers, and personalized neurodevelopmental medicine, whose short-term clinical feasibility remains uncertain.

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References

1. Balaskas N, Ribeiro A, Panovska J, et al. Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube. Cell. 2012 Jan 20;148(1-2):273-84.

2. Curchoe CL, Rizzino A, Wylie C. Engineering human neuronal diversity: morphogens and stem cell models. Trends Neurosci. 2025;48(9):711-28.

3. De Robertis EM. Spemann's organizer and the self-regulation of embryonic fields. Development. 2009 Sep;136(23):4013-20.

4. Ezin AM, Fraser SE, Bronner-Fraser M. Fate map and morphogenesis of presumptive neural crest and dorsal neural tube. Dev Biol. 2009 Mar 1;330(2):221-36.

5. Martyn I, Kondo T, Hironaka KI, et al. Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature. 2018;558(7708):132-135.

6. Rivron NC, Martinez-Arias A, Pera MF, et al. Early human development and stem cell–based human embryo models. Semin Cell Dev Biol. 2024;152:37-50.

7. Warmflash A, Sorre B, Etoc F, et al. A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat Methods. 2014;11(8):847-54.

8. Yam PT, Charron F. Signaling mechanisms of non-conventional axon guidance cues: the Shh, BMP and Wnt morphogens. Curr Opin Neurobiol. 2013;23(6):965-73.

9. Cecil CAM, Zhang Y, Nolte T. Childhood trauma and DNA methylation: A systematic review. Neurosci Biobehav Rev. 2020;112:392-409.

10. Gleason G, Liu B, Bruening S, et al. The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci USA. 2010;107(16):7592-7.

11. MacIsaac JL, Weinberg J, Beers J, et al. Maternal and infant NR3C1 and SLC6A4 epigenetic signatures are associated with infant cortisol reactivity. J Psychiatry Neurosci. 2022;47(5):E336-E348.

12. Nazzari S, Fearon P, Rice F, et al. Beyond the HPA-axis: Exploring the role of the immune system in mediating the link between childhood trauma and psychosis. Schizophr Bull. 2022;48(2):307-315.

13. Oberlander TF, Weinberg J, Papsdorf M, et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3(2):97-106.

14. Palma-Gudiel H, Córdova-Palomera A, Tornador C, et al. Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study. J Psychiatr Res. 2018;96:23-33.

15. Provenzi L, Giorda R, Beri S, et al. SLC6A4 methylation as an epigenetic marker of life stress exposures in humans: A systematic review of literature. Neurosci Biobehav Rev. 2016;71:380-395.

16. de Moor MHM, van den Berg SM, Verweij KJH, et al. Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder. JAMA Psychiatry. 2015;72(7):642-50.

17. Gupta P, Wray NR, Medland SE, et al. A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology. Nat Hum Behav. 2024;8(8):124-39.

18. Nagel M, Watanabe K, Stringer S, et al. Item-level genome-wide association study of the Alcohol Use Disorders Identification Test in three population-based cohorts. Am J Psychiatry. 2018;175(3):235-244.

19. Zwir I, Arnedo J, Del-Val C, et al. Uncovering the complex genetics of human character. Mol Psychiatry. 2020;25(10):2295-2312.

20. Komasi S, Rezaei F, Hemmati A, et al. Comprehensive meta-analysis of associations between temperament and character traits in Cloninger’s psychobiological theory and mental disorders. J Int Med Res. 2022;50(1):3000605211070766.

21. Ormel J, Hartman CA, Snieder H. The genetics of depression: successful genome-wide association studies introduce new challenges. Transl Psychiatry. 2019;9(1):114.

22. Barker DJP. The developmental origins of adult disease. J Am Coll Nutr. 2004;23(6 Suppl):588S-595S.

23. Glover V, O'Connor TG, O'Donnell K. Prenatal stress and the programming of the HPA axis. Neurosci Biobehav Rev. 2010;35(1):17-22.