The Expression of Hypoxia-Induced Gene 1 (Higd1a) in the Central Nervous System of Male and Female Rats Differs According to Age
HIGD1A (hypoxia-induced gene domain protein-1a), a mitochondrial inner membrane protein present in various cell types, has been mainly associated with anti-apoptotic processes in response to stressors. Our previous findings have shown that Higd1a mRNA is widely expressed across the central nervous system (CNS), exhibiting an increasing expression in the spinal cord from postnatal day 1 (P1) to 15 (P15) and changes in the distribution pattern from P1 to P90. During the first weeks of postnatal life, the great plasticity of the CNS is accompanied by cell death/survival decisions. So we first describe HIGD1A expression throughout the brain during early postnatal life in female and male pups. Secondly, based on the fact that in some areas this process is influenced by the sex of individuals, we explore HIGD1A expression in the sexual dimorphic nucleus (SDN) of the medial preoptic area, a region that is several folds larger in male than in female rats, partly due to sex differences in the process of apoptosis during this period. Immunohistochemical analysis revealed that HIGD1A is widely but unevenly expressed throughout the brain. Quantitative Western blot analysis of the parietal cortex, diencephalon, and spinal cord from both sexes at P1, P5, P8, and P15 showed that the expression of this protein is predominantly high and changes with age but not sex. Similarly, in the sexual dimorphic nucleus, the expression of HIGD1A varied according to age, but we were not able to detect significant differences in its expression according to sex. Altogether, these results suggest that HIGD1A protein is expressed in several areas of the central nervous system following a pattern that quantitatively changes with age but does not seem to change according to sex.
KeywordsHIGD1A Gene expression CNS Postnatal neural maturation Sex differences
The authors wish to thank Héctor Rodríguez, Joel González and Enzo Cavelli for their excellent animal care, Dr. Inés Pose for assistance in histological analysis, and Dr. Adriana Parodi for her helpful advice.
This work was supported in part by the Agencia Nacional de Investigación e Innovación (ANII) of Uruguay (grant number FCE_2_2011_1_6459) and Comisión Sectorial de Investigación Científica (Universidad de la República, Uruguay).
Compliance with Ethical Standards
Animal care and experimental procedures were performed in accordance with the Uruguayan law (Law No. 18611) on the use and care of laboratory animals, and the Ethical Committee of Facultad de Ciencias approved this study (exp.240011-002308-14).
- Aldridge GM, Podrebarac DM, Greenough WT, Weiler IJ (2008) The use of total protein stains as loading controls: an alternative to high-abundance single-protein controls in semi-quantitative immunoblotting. J Neurosci Methods 172:250–254. https://doi.org/10.1016/j.jneumeth.2008.05.003 CrossRefPubMedPubMedCentralGoogle Scholar
- Ameri K, Jahangiri A, Rajah AM, Tormos KV, Nagarajan R, Pekmezci M, Nguyen V, Wheeler ML, Murphy MP, Sanders TA, Jeffrey SS, Yeghiazarians Y, Rinaudo PF, Costello JF, Aghi MK, Maltepe E (2015) HIGD1A regulates oxygen consumption, ROS production, and AMPK activity during glucose deprivation to modulate cell survival and tumor growth. Cell Rep 10:891–899. https://doi.org/10.1016/j.celrep.2015.01.020 CrossRefGoogle Scholar
- Ameri K, Rajah AM, Nguyen V, Sanders TA, Jahangiri A, DeLay M, Donne M, Choi HJ, Tormos KV, Yeghiazarians Y, Jeffrey SS, Rinaudo PF, Rowitch DH, Aghi M, Maltepe E (2013) Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress. PLoS One 8:e62758. https://doi.org/10.1371/journal.pone.0062758 CrossRefPubMedPubMedCentralGoogle Scholar
- An HJ, Shin H, Jo SG, Kim YJ, Lee JO, Paik SG, Lee H (2011) The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation. Biochim Biophys Acta - Mol Cell Res 1813:2088–2098. https://doi.org/10.1016/j.bbamcr.2011.07.017 CrossRefGoogle Scholar
- Chadwick W, Boyle JP, Zhou Y, Wang L, Park SS, Martin B, Wang R, Becker KG, Wood WH, Zhang Y, Peers C, Maudsley S (2011) Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes. PLoS One 6:e21638. https://doi.org/10.1371/journal.pone.0021638 CrossRefPubMedPubMedCentralGoogle Scholar
- Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Grogan GM, Mauriac L, Katsaros D, Molina F, Theillet C, Darbon JM (2008) A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer. Clin Cancer Res 14:1744–1752. https://doi.org/10.1158/1078-0432.CCR-07-1833 CrossRefPubMedPubMedCentralGoogle Scholar
- Denko N, Schindler C, Koong A, Laderoute C, Green C, Giaccia A (2000) Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin Cancer Res 6:480–487Google Scholar
- Forger NG (2009) Control of cell number in the sexually dimorphic brain and spinal cord. J Neuroendocrinol 21:393–399. https://doi.org/10.1111/j.1365-2826.2009.01825.x.Control CrossRefPubMedPubMedCentralGoogle Scholar
- Hayashi H, Nakagami H, Takeichi M, Shimamura M, Koibuchi N, Oiki E, Sato N, Koriyama H, Mori M, Gerardo Araujo R, Maeda A, Morishita R, Tamai K, Kaneda Y (2012) HIG1, a novel regulator of mitochondrial γ - secretase, maintains normal mitochondrial function. FASEB J 26:2306–2317. https://doi.org/10.1096/fj.11-196063 CrossRefPubMedGoogle Scholar
- Hayashi T, Asano Y, Shintani Y, Aoyama H, Kioka H, Tsukamoto O, Hikita M, Shinzawa-Itoh K, Takafuji K, Higo S, Kato H, Yamazaki S, Matsuoka K, Nakano A, Asanuma H, Asakura M, Minamino T, Goto YI, Ogura T, Kitakaze M, Komuro I, Sakata Y, Tsukihara T, Yoshikawa S, Takashima S (2015) Higd1a is a positive regulator of cytochrome c oxidase. Proc Natl Acad Sci 112:1553–1558. https://doi.org/10.1073/pnas.1419767112 CrossRefPubMedGoogle Scholar
- Jacobson CD, Davis FC, Gorski RA (1985) Formation of the sexually dimorphic nucleus of the preoptic area: neuronal growth, migration and changes in cell number. Science 21:7–18Google Scholar
- Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chi Chin M, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Feng Yuan X, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176. https://doi.org/10.1038/nature05453 CrossRefPubMedGoogle Scholar
- Ling K, Hewitt CA, Beissbarth T, Hyde L, Banerjee K, Cheah P, Cannon PZ, Hahn CN, Thomas PQ, Smyth GK, Tan S, Thomas T, Scott HS (2009) Molecular networks involved in mouse cerebral corticogenesis and spatio-temporal regulation of Sox4 and Sox11 novel antisense transcripts revealed by transcriptome profiling. Genome Biol 10(10):R104. https://doi.org/10.1186/gb-2009-10-10-r104 CrossRefPubMedPubMedCentralGoogle Scholar
- Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019 CrossRefPubMedPubMedCentralGoogle Scholar
- Stansberg C, Vik-mo AO, Holdhus R, Breilid H, Srebro B, Petersen K, Jorgensen HA, Jonassen I, Steen VM (2007) Gene expression profiles in rat brain disclose CNS signature genes and regional patterns of functional specialisation 17:1–17. https://doi.org/10.1186/1471-2164-8-94 CrossRefPubMedPubMedCentralGoogle Scholar
- Strogolova V, Furness A, Robb-McGrath M, Garlich J, Stuart RA (2012) Rcf1 and Rcf2, members of the hypoxia-induced gene 1 protein family, are critical components of the mitochondrial cytochrome bc1-cytochrome c oxidase supercomplex. Mol Cell Biol 32:1363–1373. https://doi.org/10.1128/MCB.06369-11 CrossRefPubMedPubMedCentralGoogle Scholar
- Vinay L, Ben-Mabrouk F, Brocard F, Clarac F, Jean-Xavier C, Pearlstein E, Pflieger JF (2005) Perinatal development of the motor systems involved in postural control. In: Neural Plast, vol 12, pp 131–139Google Scholar
- Yu Y, Fuscoe JC, Zhao C, Guo C, Jia M, Qing T, Bannon DI, Lancashire L, Bao W, du T, Luo H, Su Z, Jones WD, Moland CL, Branham WS, Qian F, Ning B, Li Y, Hong H, Guo L, Mei N, Shi T, Wang KY, Wolfinger RD, Nikolsky Y, Walker SJ, Duerksen-Hughes P, Mason CE, Tong W, Thierry-Mieg J, Thierry-Mieg D, Shi L, Wang C (2014) A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages. Nat Commun 5:3230. https://doi.org/10.1038/ncomms4230 CrossRefPubMedPubMedCentralGoogle Scholar