Abstract
Glucocorticoids, the most downstream effectors of the hypothalamus–pituitary–adrenal axis, are one of main mediators of the stress reaction. Indeed, exposure to high levels of stress-triggered glucocorticoids is detrimental to brain development associated with abnormal behaviors in experimental animals and the risk of psychiatric disorders in humans. Despite the wealth of this knowledge, the cellular and molecular mechanisms underlying the detrimental effects of glucocorticoids on brain development remain unclear. Here, we show that excess glucocorticoids retard the radial migration of post-mitotic neurons during the development of the cerebral cortex, and identify an actin regulatory protein, caldesmon, as the glucocorticoids’ main target. The upregulation of caldesmon expression is mediated by glucocorticoid receptor-dependent transcription of the CALD1 gene encoding caldesmon. This upregulated caldesmon negatively controls the function of myosin II, leading to changes in cell shape and migration. The depletion of caldesmon in vivo impairs radial migration. The overexpression of caldesmon also causes delayed radial migration during cortical development, mimicking the excessive glucocorticoid-induced retardation of radial migration. We conclude that an appropriate range of caldesmon expression is critical for radial migration, and that its overexpression induced by excess glucocorticoid retards radial migration during cortical development. Thus, this study provides a novel insight into the underlying mechanism of glucocorticoid-related neurodevelopmental disorders.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
McEwen BS . Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005; 54: 20–23.
Manji HK, Drevets WC, Charney DS . The cellular neurobiology of depression. Nat Med 2001; 7: 541–547.
Koenig JI, Kirkpatrick B, Lee P . Glucocorticoid hormones and early brain development in schizophrenia. Neuropsychopharmacology 2002; 27: 309–318.
De kloet ER, Joëls M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.
McEwen BS . Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22: 105–122.
Cerqueira JJ, Pêgo JM, Taipa R, Bessa JM, Almeida OF, Sousa N . Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci 2005; 25: 7792–7800.
Mitra R, Sapolsky RM . Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc Natl Acad Sci USA 2008; 105: 5573–5578.
Bakker JM, Bel FV, Heijnen CJ . Neonatal glucocorticoids and the developing brain: short-term treatment with life-long consequences? Trends Neurosci 2001; 24: 649–653.
Stéphane VS, Borradori-Tolsa C, Vauthay DM, Lodygensky G, Lazeyras F, Hüppi PS . Impact of intrauterine growth restriction and glucocorticoids on brain development: insights using advanced magnetic resonance imaging. Mol Cell Endocrinol 2006; 254-255: 163–171.
Weinstock M . The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 2008; 32: 1073–1086.
Becker JB, Monteqqia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R et al. Stress and disease: is being female a predisposing factor? J Neurosci 2007; 27: 11851–11855.
Phillips NK, Hammen CL, Brennan PA, Najman JM, Bor W . Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents. J Abnorm Child Psychol 2005; 33: 13–24.
Flagel SB, Vázquez DM, Watson Jr SJ, Neal Jr CR . Effects of tapering neonatal dexamethasone on rat growth, neurodevelopment, and stress response. Am J Physiol Regul Integr Comp Physiol 2002; 282: R55–R63.
Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA . Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999; 94: 213–218.
Modi N, Lewis H, Al-Naqeeb N, Ajayi-Obe M, Doré CJ, Rutherford M . The effects of repeated antenatal glucocorticoid therapy on the developing brain. Pediatri Res 2001; 50: 581–585.
Dehay C, Kennedy H . Cell-cycle control and cortical development. Nat Rev Neurosci 2007; 8: 438–450.
Ayala R, Shu T, Tsai LH . Trekking across the brain: the journey of neuronal migration. Cell 2007; 128: 29–43.
Gleeson JG, Walsh CA . Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci 2000; 8: 352–359.
Lavado-Autric R, Ausó E, García-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 2003; 111: 1073–1082.
Ausó E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P . A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 2004; 145: 4037–4047.
Konno J, Yoshida S, Ina A, Ohmomo H, Shutoh F, Nogami H et al. Upregulated expression of neuropeptide Y in hypothalamic–pituitary system of rats by chronic dexamethasone administration. Neurosci Res 2008; 60: 259–265.
Wong EY, Herbert J . Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur J Neurosci 2005; 22: 785–792.
Mayanagi T, Morita T, Hayashi K, Fukumoto K, Sobue K . Glucocorticoid receptor-mediated expression of caldesmon regulates cell migration via the reorganization of the actin cytoskeleton. J Biol Chem 2008; 283: 31183–31196.
Konno D, Yoshimura S, Hori K, Maruoka H, Sobue K . Involvement of the phosphatidylinositol 3-kinase/rac1 and cdc42 pathways in radial migration of cortical neurons. J Biol Chem 2005; 280: 5082–5088.
Li HP, Honma S, Miki T, Takeuchi Y, Kawano H . Multiple defects in the formation of rat cortical axonal pathways following prenatal X-ray irradiation. Eur J Neurosci 2005; 21: 1847–1858.
Giorno R . A comparison of two immunoperoxidase staining methods based on the avidin-biotin interaction. Diagn Immunol 1984; 2: 161–166.
Mishima T, Sakatani S, Hirase H . Intracellular labeling of single cortical astrocytes in vivo. J Neurosci Methods 2007; 166: 32–40.
Matthews SG . Antenatal glucocorticoids and the developing brain; mechanisms of action. Semin Neonatol 2001; 6: 309–317.
Diaz R, Brown RW, Seckl JR . Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11β-Hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions. J Neurosci 1998; 18: 2570–2580.
Slotkin TA, Kreider ML, Tate CA, Seidler FJ . Prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems. Neuropsychopharmacology 2006; 31: 904–911.
Sobue K, Sellers JR . Caldesmon, a novel regulatory protein in smooth muscle and nonmuscle actomyosin systems. J Biol Chem 1991; 266: 12115–12118.
Hayashi K, Yano H, Hashida T, Takeuchi R, Takeda O, Asada K et al. Genomic structure of the human caldesmon gene. Proc Natl Acad Sci USA 1992; 89: 12122–12126.
Bowers SL, Bilbo SD, Dhabhar FS, Nelson RJ . Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun 2008; 22: 105–113.
Morita T, Mayanagi T, Sobue K . Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling. J Cell Biol 2007; 179: 1027–1042.
Heine VM, Rowitch DH . Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11âHSD2-dependent mechanism. J Clin Invest 2009; 119: 267–277.
Sobue K, Muramoto Y, Fujita M, Kakiuchi S . Purification of a calmodulin-binding protein from chicken gizzard that interacts with F-actin. Proc Natl Acad Sci USA 1981; 78: 5652–5655.
Hayashi K, Nakamura S, Nishida W, Sobue K . Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription. Mol Cell Biol 2006; 26: 9456–9470.
Castellino F, Heuser J, Marchetti S, Bruno B, Luini A . Glucocorticoid stabilization of actin filaments: a possible mechanism for inhibition of corticotropin release. Proc Natl Acad Sci USA 1992; 89: 3775–3779.
Antonow-Schlorke I, Schwab M, Li C, Nathanielsz PW . Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain. J Physiol 2003; 547: 117–123.
Cereseto M, Reinés A, Ferrero A, Sifonios L, Rubio M, Wikinski S . Chronic treatment with high doses of corticosterone decreases cytoskeletal proteins in the rat hippocampus. Eur J Neurosci 2006; 24: 3354–3364.
Datson NA, Van der Perk J, De Kloet ER, Vreugdenhil E . Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. Eur J Neurosci 2001; 14: 675–689.
Alfonso J, Pollevick GD, Van Der Hart MG, Flüqqe G, Fuchs E, Frasch AC . Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus. Eur J Neurosci 2004; 19: 659–666.
Morita T, Mayanagi T, Yoshio T, Sobue K . Changes in the balance between caldesmon regulated by p21-activated kinases and the Arp2/3 complex govern podosome formation. J Biol Chem 2007; 282: 8454–8463.
Even-Ram S, Doyle AD, Conti MA, Matsumoto K, Adelstein RS, Yamada KM . Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nat Cell Biol 2007; 9: 299–309.
Tabata H, Nakajima K . Multipolar migration: the third mode of radial neuronal migration in the developing cerebral cortex. J Neurosci 2003; 23: 9996–10001.
Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR . Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 2004; 7: 136–144.
Nagano T, Yoneda T, Hatanaka Y, Kubota C, Murakami F, Sato M . Filamin A-interacting protein (FILIP) regulates cortical cell migration out of the ventricular zone. Nat Cell Biol 2002; 4: 495–501.
Tsai JW, Chen Y, Krieqstein AR, Vallee RB . LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J Cell Biol 2005; 170: 935–945.
Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ . RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci 2003; 6: 1277–1283.
Xie Z, Tsai LH . Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Cell Cycle 2004; 3: 108–110.
Ohshima T, Hirasawa M, Tabata H, Mutoh T, Adachi T, Suzuki H et al. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development 2007; 134: 2273–2282.
Meaney MJ, Szyf M . Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci 2005; 28: 456–463.
Acknowledgements
We thank Dr S Furukawa (Gifu Pharmaceutical University) for advice on the in utero electroporation technique. This research was supported by Grant-in-Aids for Scientific Research (20240038) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KS).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)
Supplementary information
Rights and permissions
About this article
Cite this article
Fukumoto, K., Morita, T., Mayanagi, T. et al. Detrimental effects of glucocorticoids on neuronal migration during brain development. Mol Psychiatry 14, 1119–1131 (2009). https://doi.org/10.1038/mp.2009.60
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2009.60
Keywords
This article is cited by
-
Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer
Oncogenesis (2023)
-
Caldesmon controls stress fiber force-balance through dynamic cross-linking of myosin II and actin-tropomyosin filaments
Nature Communications (2022)
-
Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain
Cellular and Molecular Neurobiology (2022)
-
Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids
Molecular Psychiatry (2021)
-
Neurobiology of zinc and its role in neurogenesis
European Journal of Nutrition (2021)