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Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Evgeniia Kazymova (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Evgeniia Kazymova (send email)||Under Development: Contributions and Comments Welcome|
|Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Evgeniia Kazymova (send email)||Open for adoption||Under Development|
Life Stage Applicability
|During brain development||Moderate|
Key Event Relationship Description
The basic biological processes that link gene regulation in the structural formation and function of all organs of the body are similar throughout the developing organism. In the developing brain, genes encode proteins critical for developmental events intrinsic to structural development (e.g., neurogenesis, neuronal migration, synaptogenesis, myelination). The development of the hippocampus is no exception to this general rule of biology.
Evidence Collection Strategy
Evidence Supporting this KER
The overall weight of evidence is moderate for a direct linkage between perturbation of the expression of genes in brain (and in hippocampus specifically) and neuroanatomical abnormalities. It is widely acknowledged that the development of the structure of the hippocampus is under the control of hippocampal gene expression. However, while an extensive body of literature exists linking some genes to hippocampal structure, there is no complete compendium on the total number of genes involved, nor direct causative links between the myriad of genes and the intricate development (both timing and location) of the majority of hippocampal structure.
The biological plausibility of this KER is rated as strong. It is well established that gene regulation controls brain development. This also applies to the development of the hippocampus, where nuclear thyroid receptors that regulate gene transcription, directly or indirectly via transcription factor regulation, to control translation.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some uncertainties. Few studies exist that report both gene expression changes and structural changes in the hippocampus in same study to provide direct causative evidence for this KER. Lacking also is the specific suite of genes that are altered in the hippocampus at particular developmental times that are causal to the structural defects reported. For future research, it is critical to generate data in which the upstream KE is modulated in a ‘dose-response’ manner to better support the causative relationship. Significant data gaps also exist for basic fetal hippocampal development.
Known modulating factors
There are no data on the quantitative linkages between gene expression changes and altered hippocampal anatomy.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The majority of data in support of this KER is from rodent models. The evolutionary conservation of thyroid receptors (Holzer et al., 2017) coupled with their role in TR regulated gene transcription in neurodevelopment, suggests that this KER may also be applicable to other species.
Auso E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037-4047.
Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM. Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb Cortex. 2010 20(6):1462-75.
Castrén ML, Castrén E. BDNF in fragile X syndrome. Neuropharmacology. 2014 76:729-36.
Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V, Nicolis SK. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci. 2009 12(10):1248-56.
Frotscher M. Role for Reelin in stabilizing cortical architecture. Trends Neurosci. 2010 Sep;33(9):407-14.
Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992 Dec 18;258(5090):1903-10.
Holzer G, Roux N, Laudet V. Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling. Mol Cell Endocrinol. 2017 Mar 22. pii: S0303-7207(17)30191-0. doi: 10.1016/j.mce.2017.03.021. [Epub ahead of print]
Khalaf-Nazzal R, Bruel-Jungerman E, Rio JP, Bureau J, Irinopoulou T, Sumia I, Roumegous A, Martin E, Olaso R, Parras C, Cifuentes-Diaz C, Francis F. Organelle and cellular abnormalities associated with hippocampal heterotopia in neonatal doublecortin knockout mice. PLoS One. 2013 Sep 2;8(9):e72622.
Lee KH, Lee H, Yang CH, Ko JS, Park CH, Woo RS, Kim JY, Sun W, Kim JH, Ho WK, Lee SH. Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergicSynapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells ofPostnatal Hippocampus. J Neurosci. 2015 Dec 16;35(50):16479-93.
Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required fordevelopment of the mammalian hippocampus. Development. 2000 Feb;127(3):457-67.
Lessmann V, Stroh-Kaffei S, Steinbrecher V, Edelmann E, Brigadski T, Kilb W, Luhmann HJ. The expression mechanism of the residual LTP in the CA1 region of BDNF k.o. mice is insensitive to NO synthase inhibition. Brain Res. 2011 1391:14-23.
Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H.The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid. 2010 Aug;20(8):909-15.
Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, Godbole MM (2012) Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 237:477-488.
Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM. 2011. Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cerebral Cortex.11-21.
Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35(8-9):664-72.
Shin JH, Kim YN, Kim IY, Choi DH, Yi SS, Seong JK. Increased Cell Proliferations and Neurogenesis in the Hippocampal Dentate Gyrus of Ahnak Deficient Mice. Neurochem Res. 2015 Jul;40(7):1457-62.
Skucas VA, Mathews IB, Yang J, Cheng Q, Treister A, Duffy AM, Verkman AS, Hempstead BL, Wood MA, Binder DK, Scharfman HE. Impairment of select forms ofspatial memory and neurotrophin-dependent synaptic plasticity by deletion ofglial aquaporin-4. J Neurosci. 2011 31(17):6392-7.
Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A,Lopez-Rojas J, Montag D, Angenstein F, Bär J, D'Hanis W, Roskoden T, MikhaylovaM, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR.A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impared BDNFSignaling in Dendritogenesis. PLoS Genet. 2016 Mar 15;12(3):e1005907
Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014 Oct;15(10):655-69.
Takei Y, Kikkawa YS, Atapour N, Hensch TK, Hirokawa N. Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A. J Neurosci. 2015 35(47):15539-54.