Hedgehog信号通路在动物卵巢卵泡发育和类固醇生成中的调控作用

doi:10.11843/j.issn.0366-6964.2025.03.001

Abstract

Abstract:

The Hedgehog (HH) signaling pathway is one of the key pathways involved in embryogenesis, widely distributed and highly conserved throughout the evolutionary process from fruit flies to humans, playing a crucial role in the development of various organs. Studies have indicated that the HH signaling pathway plays an important regulatory role in the growth of ovarian follicles, proliferation of granulosa cells, maturation of oocytes, synthesis of steroid hormones, and process of ovulation. Based on the existing research findings, this article provides a detailed review of the regulatory functions of the HH signaling pathway in the growth of ovarian follicles, maturation of oocytes, ovulation, and synthesis of steroid hormones, as well as an overview of the latest research trends on several ovarian diseases that lead to a decline in fertility due to abnormalities in the HH signaling pathway, aiming to provide theoretical support for enhancing female reproductive capacity and the treatment of ovarian diseases.

Key words: Hedgehog signaling pathway, ovary, fertility, follicle development, steroidogenesis

CLC Number:

MIELIE·Madaniyati , SUN Meng, CHU Guiyan. The Regulatory Function of the Hedgehog Signaling Pathway in Follicle Development and Steroidogenesis of Animal Ovary[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(3): 969-978.

Figures/Tables 3

Fig. 1

Table 1

Table 2

References 62

1	LI L Y , SHI X J , SHI Y , et al. The signaling pathways involved in ovarian follicle development[J]. Front Physiol, 2021, 12, 730196. doi: 10.3389/fphys.2021.730196
2	YAO X L , EI-SAMAHY M A , XIAO S H , et al. CITED4 mediates proliferation, apoptosis and steroidogenesis of Hu sheep granulosa cells in vitro[J]. Reproduction, 2021, 161 (3): 255- 267. doi: 10.1530/REP-20-0427
3	ZHANG Y X , BEACHY P A . Cellular and molecular mechanisms of Hedgehog signalling[J]. Nat Rev Mol Cell Biol, 2023, 24 (9): 668- 687. doi: 10.1038/s41580-023-00591-1
4	DILOWER I , NILOY A J , KUMAR V , et al. Hedgehog signaling in gonadal development and function[J]. Cells, 2023, 12 (3): 358. doi: 10.3390/cells12030358
5	HUANG C C J , YAO H H C . Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs[J]. Mol Reprod Dev, 2010, 77 (6): 489- 496. doi: 10.1002/mrd.21174
6	FINCO I , LAPENSEE C R , KRILL K T , et al. Hedgehog signaling and steroidogenesis[J]. Annu Rev Physiol, 2015, 77, 105- 129. doi: 10.1146/annurev-physiol-061214-111754
7	SARI I N , PHI L T H , JUN N , et al. Hedgehog signaling in cancer: a prospective therapeutic target for eradicating cancer stem cells[J]. Cells, 2018, 7 (11): 208. doi: 10.3390/cells7110208
8	SKODA A M , SIMOVIC D , KARIN V , et al. The role of the Hedgehog signaling pathway in cancer: a comprehensive review[J]. Bosn J Basic Med Sci, 2018, 18 (1): 8- 20. doi: 10.17305/bjbms.2018.2756
9	SIGAFOOS A N , PARADISE B D , FERNANDEZ-ZAPICO M E . Hedgehog/GLI signaling pathway: transduction, regulation, and implications for disease[J]. Cancers (Basel), 2021, 13 (14): 3410. doi: 10.3390/cancers13143410
10	JIA Y F , WANG Y S , XIE J W . The Hedgehog pathway: role in cell differentiation, polarity and proliferation[J]. Arch Toxicol, 2015, 89 (2): 179- 191. doi: 10.1007/s00204-014-1433-1
11	HUI C C , ANGERS S . Gli proteins in development and disease[J]. Annu Rev Cell Dev Biol, 2011, 27, 513- 537. doi: 10.1146/annurev-cellbio-092910-154048
12	LIU C , RODRIGUEZ K F , BROWN P R , et al. Reproductive, physiological, and molecular outcomes in female mice deficient in Dhh and Ihh[J]. Endocrinology, 2018, 159 (7): 2563- 2575.
13	MONKKONEN T , LEWIS M T . New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer[J]. Biochim Biophys Acta Rev Cancer, 2017, 1868 (1): 315- 332. doi: 10.1016/j.bbcan.2017.06.003
14	FRANCO H L , YAO H H C . Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation[J]. Chromosome Res, 2012, 20 (1): 247- 258.
15	MEHTA P , SINGH P , GUPTA N J , et al. Mutations in the desert hedgehog (DHH) gene in the disorders of sexual differentiation and male infertility[J]. J Assist Reprod Genet, 2021, 38 (7): 1871- 1878.
16	JOHANSSON H K L , SVINGEN T . Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: is there a link to endocrine disrupting chemicals?[J]. Curr Res Toxico, 2020, 1, 116- 123.
17	BIAN Y H , HAHN H , UHMANN A . The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis[J]. Front Endocrinol (Lausanne), 2023, 14, 1219018.
18	SEN A , HOFFMANN H M . Role of core circadian clock genes in hormone release and target tissue sensitivity in the reproductive axis[J]. Mol Cell Endocrinol, 2020, 501, 110655.
19	RICHARDS J S , REN Y A , CANDELARIA N , et al. Ovarian follicular theca cell recruitment, differentiation, and impact on fertility: 2017 update[J]. Endocr Rev, 2018, 39 (1): 1- 20. doi: 10.1210/er.2017-00164
20	LIU C , PENG J , MATZUK M M , et al. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells[J]. Nat Commun, 2015, 6, 6934. doi: 10.1038/ncomms7934
21	REN Y , COWAN R G , MIGONE F F , et al. Overactivation of hedgehog signaling alters development of the ovarian vasculature in mice[J]. Biol Reprod, 2012, 86 (6): 174.
22	CHEN X , TUKACHINSKY H , HUANG C H , et al. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum[J]. J Cell Biol, 2011, 192 (5): 825- 838. doi: 10.1083/jcb.201008090
23	JIANG Y , ZHU D T , LIU W F , et al. Hedgehog pathway inhibition causes primary follicle atresia and decreases female germline stem cell proliferation capacity or stemness[J]. Stem Cell Res Ther, 2019, 10 (1): 198. doi: 10.1186/s13287-019-1299-5
24	SINGH T , LEE E H , HARTMAN T R , et al. Opposing action of hedgehog and insulin signaling balances proliferation and autophagy to determine follicle stem cell lifespan[J]. Dev Cell, 2018, 46 (6): 720- 734.e6. doi: 10.1016/j.devcel.2018.08.008
25	WANG D C , HUANG J C , LO N W , et al. Sonic Hedgehog promotes in vitro oocyte maturation and term development of embryos in Taiwan native goats[J]. Theriogenology, 2017, 103, 52- 58. doi: 10.1016/j.theriogenology.2017.07.029
26	LEE S , JIN J X , TAWEECHAIPAISANKUL A , et al. Melatonin influences the sonic hedgehog signaling pathway in porcine cumulus oocyte complexes[J]. J Pineal Res, 2017, 63 (3): e12424. doi: 10.1111/jpi.12424
27	LEE S , KANG H G , JEONG P S , et al. Effect of oocyte quality assessed by brilliant cresyl blue (BCB) staining on cumulus cell expansion and sonic hedgehog signaling in porcine during in vitro maturation[J]. Int J Mol Sci, 2020, 21 (12): 4423. doi: 10.3390/ijms21124423
28	LIU Y , WEI Z Y , HUANG Y F , et al. Cyclopamine did not affect mouse oocyte maturation in vitro but decreased early embryonic development[J]. Anim Sci J, 2014, 85 (9): 840- 847. doi: 10.1111/asj.12220
29	GUO Q , XUAN M F , LUO Z B , et al. Baicalin improves the in vitro developmental capacity of pig embryos by inhibiting apoptosis, regulating mitochondrial activity and activating sonic hedgehog signaling[J]. Mol Hum Reprod, 2019, 25 (9): 538- 549. doi: 10.1093/molehr/gaz036
30	JEONG P S , KANG H G , SONG B S , et al. Restoration of developmental competence in low-quality porcine cumulus-oocyte complexes through the supplementation of sonic hedgehog protein during in vitro maturation[J]. Animals (Basel), 2023, 13 (6): 1001.
31	JOO Y E , JEONG P S , LEE S , et al. Anethole improves the developmental competence of porcine embryos by reducing oxidative stress via the sonic hedgehog signaling pathway[J]. J Anim Sci Biotechnol, 2023, 14 (1): 32.
32	GUO Q , LI S , WANG X , et al. Paeoniflorin improves the in vitro maturation of benzo(a)pyrene treated porcine oocytes via effects on the sonic hedgehog pathway[J]. Theriogenology, 2022, 180, 72- 81.
33	AAD P Y , ECHTERNKAMP S E , SYPHERD D D , et al. The hedgehog system in ovarian follicles of cattle selected for twin ovulations and births: evidence of a link between the IGF and hedgehog systems[J]. Biol Reprod, 2012, 87 (4): 79.
34	PARK Y , PARK Y B , LIM S W , et al. Time series ovarian transcriptome analyses of the porcine estrous cycle reveals gene expression changes during steroid metabolism and corpus luteum development[J]. Animals (Basel), 2022, 12 (3): 376.
35	TANG C , PAN Y B , LUO H , et al. Hedgehog signaling stimulates the conversion of cholesterol to steroids[J]. Cell Signal, 2015, 27 (3): 487- 497.
36	SIEBOLD C , ROHATGI R . The inseparable relationship between cholesterol and hedgehog signaling[J]. Annu Rev Biochem, 2023, 92, 273- 298.
37	JING J J , WU Z X , WANG J H , et al. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies[J]. Sig Transduct Target Ther, 2023, 8 (1): 315.
38	LI Y , XIONG G H , TAN J , et al. Aberrant activation of the Hedgehog signaling pathway in granulosa cells from patients with polycystic ovary syndrome[J]. Bioengineered, 2021, 12 (2): 12123- 12134.
39	XU X H , ZHANG T R , MOKOU M , et al. Follistatin-like 1 as a novel adipomyokine related to insulin resistance and physical activity[J]. J Clin Endocrinol Metab, 2020, 105 (12): dgaa629.
40	ZHOU X , WANG Y P , CHEN W Y , et al. Circulating HHIP levels in women with insulin resistance and PCOS: effects of physical activity, cold stimulation and anti-diabetic drug therapy[J]. J Clin Med, 2023, 12 (3): 888.
41	ZHANG J J , CHEN Q , DU D F , et al. Can ovarian aging be delayed by pharmacological strategies?[J]. Aging (Albany NY), 2019, 11 (2): 817- 832.
42	VOLLENHOVEN B , HUNT S . Ovarian ageing and the impact on female fertility[J]. F1000Research, 2018, 7, 1835.
43	ATA B , SEYHAN A , SELI E . Diminished ovarian reserve versus ovarian aging: overlaps and differences[J]. Curr Opin Obstet Gynecol, 2019, 31 (3): 139- 147.
44	SHEIKHANSARI G , AGHEBATI-MALEKI L , NOURI M , et al. Current approaches for the treatment of premature ovarian failure with stem cell therapy[J]. Biomed Pharmacother, 2018, 102, 254- 262.
45	ESMAEILIAN Y , ATALAY A , ERDEMLI E . Putative germline and pluripotent stem cells in adult mouse ovary and their in vitro differentiation potential into oocyte-like and somatic cells[J]. Zygote, 2017, 25 (3): 358- 375.
46	EBRAHIMI M , AKBARI ASBAGH F . The role of autoimmunity in premature ovarian failure[J]. Iran J Reprod Med, 2015, 13 (8): 461- 472.
47	JIANG Y , ZHANG Z Y , CHA L J , et al. Resveratrol plays a protective role against premature ovarian failure and prompts female germline stem cell survival[J]. Int J Mol Sci, 2019, 20 (14): 3605.
48	TEMPLEMAN N M , COTA V , KEYES W , et al. CREB non-autonomously controls reproductive aging through hedgehog/patched signaling[J]. Dev Cell, 2020, 54 (1): 92- 105.e5.
49	SIEGEL R L , MILLER K D , WAGLE N S , et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73 (1): 17- 48.
50	LI H X , LI J H , FENG L M . Hedgehog signaling pathway as a therapeutic target for ovarian cancer[J]. Cancer Epidemiol, 2016, 40, 152- 157.
51	KAYE S B , FEHRENBACHER L , HOLLOWAY R , et al. A phase Ⅱ, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission[J]. Clin Cancer Res, 2012, 18 (23): 6509- 6518.
52	SONG X L , YAN L Y , LU C L , et al. Activation of hedgehog signaling and its association with cisplatin resistance in ovarian epithelial tumors[J]. Oncol Lett, 2018, 15 (4): 5569- 5576.
53	STEG A D , KATRE A A , BEVIS K S , et al. Smoothened antagonists reverse taxane resistance in ovarian cancer[J]. Mol Cancer Ther, 2012, 11 (7): 1587- 1597.
54	BEN-HAMO R , ZILBERBERG A , COHEN H , et al. Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types[J]. npj Precis Oncol, 2019, 3, 12.
55	TASSI R A , TODESCHINI P , SIEGEL E R , et al. FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients[J]. J Exp Clin Cancer Res, 2017, 36 (1): 63.
56	ZHANG H , HU L Y , CHENG M Z , et al. The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer[J]. Oncol Rep, 2020, 44 (6): 2610- 2620.
57	MENG E H , HANNA A , SAMANT R S , et al. The impact of hedgehog signaling pathway on DNA repair mechanisms in human cancer[J]. Cancers (Basel), 2015, 7 (3): 1333- 1348.
58	HUANG R L , GU F , KIRMA N B , et al. Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers[J]. Epigenetics, 2013, 8 (6): 624- 634.
59	ZHANG K , SUN C P , ZHANG Q , et al. Sonic hedgehog-Gli1 signals promote epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway[J]. Med Oncol, 2015, 32 (1): 368.
60	ZHU Q J , YANG X , LV Y C . HERC4 modulates ovarian cancer cell proliferation by regulating SMO-elicited hedgehog signaling[J]. Biochim Biophys Acta Gen Sub, 2024, 1868 (4): 130557.
61	THAZHACKAVAYAL BABY B , KULKARNI A M , GAYAM P K R , et al. Beyond cyclopamine: targeting Hedgehog signaling for cancer intervention[J]. Arch Biochem Biophys, 2024, 754, 109952.
62	LIU Y B , HE L M , SUN M , et al. A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened[J]. Cell Chem Biol, 2024, 31 (7): 1264- 1276.e7.

卵巢生理 Ovarian physiology	作用 Function	参考文献 Reference
卵泡发育 Follicular development	HH信号通路通过调控GCs和卵母细胞之间的双向信号传导及靶基因的表达，促进卵泡细胞的增殖与分泌，维持卵泡储备，促进卵泡生长	[1, 19-23]
卵母细胞成熟 Oocyte maturation	HH信号通路通过调控卵泡干细胞的自噬和死亡，调节卵母细胞相关基因及表达，并与外源因子(如褪黑素、黄芩苷等)产生互作，降低氧化应激，促进卵母细胞成熟和胚胎发育	[24-32]
排卵 Ovulation	HH信号通过调控卵巢细胞充分分化，增强GCs对LH的反应性及与IGF系统的相互作用, 促进排卵及黄体形成	[5, 20-21, 33-34]
类固醇激素合成 Steroid hormone synthesis	HH信号的激活通过上调类固醇生成酶的表达诱导胆固醇转化为类固醇激素	[4, 12, 19, [35-36]

卵巢病理 Ovarian pathology	作用 Function	参考文献 Reference
多囊卵巢综合征 Polycystic ovarian syndrome	HH信号的异常激活可能通过调节颗粒细胞氧化应激和凋亡及其与代谢紊乱的关系促进PCOS的发生	[38-40]
卵巢早衰和卵巢功能不全Premature ovarian failure and ovarian insufficiency	HH信号通过调节卵泡发育，缓解氧化应激，增加原始卵泡数量以及促进FGSCs增殖和干性，调节卵母细胞质量和延缓生殖衰退速度	[23, 47-48]
卵巢癌 Carcinoma of ovary	HH信号通路通过DNA损伤修复、DNA甲基化和上皮-间质转化诱导耐药，抑制卵巢癌细胞的生长，并在体内抑制肿瘤的生长	[50-60]

[1]	LU Jian, MA Meng, GUO Jun, WANG Xingguo, DOU Taocun, HU Yuping, WANG Qiang, LI Yongfeng, SHAO Dan, TONG Haibing, GUO Jie, QU Liang. Studies on Key Genes and Signaling Pathways of Regulation of Energy Restriction during Rearing and Conversion to Ad libitum on the Reproductive Organ Development of Hens at the Initiation of Laying Period [J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(2): 737-754.
[2]	WANG Lei, BAI Shaocheng, WANG Sen, BAO Zhiyuan, CAI Jiawei, LIU Yan, ZHAO Bohao, WU Xinsheng, CHEN Yang. Effect of SRD5A2 on the Expression of Genes Related to Proliferation, Apoptosis and Steroid Hormone Synthesis in Rabbit Granulosa Cells [J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(1): 259-268.
[3]	Rui SHI, Shanshan LI, Hailiang ZHANG, Haibo LU, Qingxia YAN, Yi ZHANG, Shaohu CHEN, Yachun WANG. Genotype by Environment Interaction of Fertility Traits for the Holstein Cattle in China [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(9): 3968-3977.
[4]	Yaxuan MENG, Yan LIU, Jing WANG, Guoshun CHEN, Tao FENG. Research Progress in the Effect of Oxidative Stress on Ovarian Function in Female Livestock [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(7): 2825-2835.
[5]	Lirui ZHANG, Beiyu ZHANG, Yujuan LI, Yongxu LIU, Hong ZHAO, Fuchang LI, Lei LIU. Effects of Dietary Methionine Level on Wool Production Performance and Hair Follicle Development of Angora Rabbits [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(7): 3024-3031.
[6]	Xiaosong WANG, Dong LI, Shu LI, Jiali CHEN, Yongxu LIU, Hong ZHAO, Fuchang LI, Lei LIU. Effects of Dietary Different Copper Levels on Production Performance and Hair Follicle Development in Angora Rabbits [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(7): 3032-3039.
[7]	Haoran SONG, Xiaoyi FENG, Peipei ZHANG, Hang ZHANG, Yifan NIU, Zhou YU, Pengcheng WAN, Kai CUI, Xueming ZHAO. The Mechanism of Follicular Granulosa Cells in Follicular Development in Dairy Cows [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(6): 2313-2324.
[8]	Xuanyi WANG, Yawei SUN, Yuwei LONG, Liying WANG, Yuxin ZHOU, Na LI, Xuelian MA, Hongqiong ZHAO, Gang YAO. Correlation Analysis of FOXP3, FSHR, FMR1 Gene Polymorphisms and Reproductive Hormones in Infertile Cows [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(6): 2727-2740.
[9]	Ting JIANG, Wendong LI, Xingqi LI, Yu HUANG, Qigui WANG, Haiwei WANG, Chaowu YANG, Lingbin LIU. Screening Candidate Genes for Ovarian Development and Constructing Regulatory Network in Nesting Chickens by Transcriptome and Proteome [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(11): 4950-4967.
[10]	Tongtong YANG, Hailiang ZHANG, Ao WANG, Yao CHANG, Shanshan LI, Jiahe GUO, Junxing ZHANG, Yuechuan HUANG, Liyun HAN, Yu WANG, Yachun WANG. Estimation of Genetic Parameters for First Estrus Expression Traits in Holstein Cattle [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(11): 5050-5058.
[11]	Jian LU, Xiaojun JU, Xingguo WANG, Meng MA, Qiang WANG, Yongfeng LI, Taocun DOU, Yuping HU, Jun GUO, Dan SHAO, Haibing TONG, Liang QU. Effects of Metabolizable Energy Intake during Rearing on Development of Reproductive Organs, Hormone Level and Gene Expression in Ovary of Laying Hens [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(11): 5085-5100.
[12]	DUAN Xiangru, KANG Jia, YANG Ruochen, SHAN Xinyu, LI Taichun, ZHAO Wen, ZHANG Yingjie, LIU Yueqin. Effect of L-cysteine on Proliferation, Apoptosis and the Secretion of Steroid Hormone in Ovine Ovarian Granulosa Cells [J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(1): 179-191.
[13]	RU Meng, ZENG Wenhui, PENG Jianling, ZENG Qingjie, YIN Chao, CUI Yong, WEI Qing, LIANG Haiping, XIE Xianhua, HUANG Jianzhen. Research Progress on Follicles Development of Hens and Its Epigenetic Regulatory Mechanism [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(9): 3613-3622.
[14]	LI Yujuan, ZHANG Yuanming, ZHANG Beiyu, LI Fuchang, LIU Lei. Effects of Dietary Lysine Supplementation on Hair Production Performance and Hair Follicle Development of Angora Rabbits [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(5): 2013-2019.
[15]	LIAO Weili, ZHANG Xiaoke, ZENG Jianhua, YANG Linfang, LI Shuo, HU Mengting, GUO Yixuan, CHEN Zanmou, ZHANG Hao, LI Jiaqi, YUAN Xiaolong. Associations between FOXL2 Polymorphism and Several Important Economic Traits in Liangguang Spotted Pigs [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(3): 956-965.

The Regulatory Function of the Hedgehog Signaling Pathway in Follicle Development and Steroidogenesis of Animal Ovary

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 3

References 62

Related Articles 15

Recommended Articles

Metrics

Comments