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Hedgehog Signaling: Advances in Development and Cancer
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Hedgehog Signaling: Advances in Development and Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10602

Special Issue Editor

Dr. Xiaoyan Zheng

E-Mail Website
Guest Editor
Department of Anatomy and Cell Biology, The George Washington (GW) Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC 20052-20037, USA
Interests: cell signaling; development; cell culture; Drosophila
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Thirty years ago, in 1992, the Drosophila hedgehog (hh) gene was independently cloned by the research teams of Jym Mohler, Philip Beachy, Thomas Kornberg, and Saigo Kaoru. Following this discovery, three classes of vertebrate hh genes were identified: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). We now know that the Hh signaling pathway patterns a variety of organs and tissues in metazoan embryos. Defective Hh signaling during development thus leads to patterning defects, such as disrupted segmentation in Drosophila, holoprosencephaly, and other malformations in humans. Postembryonically, the Hh pathway also functions homeostatically in tissue maintenance and regeneration processes, acting on tissue stem or progenitor cells. Therefore, the postembryonic dysregulation of Hh pathway activity can result in proliferative conditions, such as malignant tumors or tissue degeneration. 

In this Special Issue, thirty years since discovering the hh gene, we invite you to advance our current knowledge on Hh signaling by contributing review articles or original research articles describing mechanistic insights at the molecular, cellular, or organismal level, as well as those providing translational value.

Dr. Xiaoyan Zheng
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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16 pages, 4530 KiB  
Article
ERβ Regulation of Indian Hedgehog Expression in the First Wave of Ovarian Follicles
by V. Praveen Chakravarthi, Iman Dilower, Subhra Ghosh, Shaon Borosha, Ryan Mohamadi, Vinesh Dahiya, Kevin Vo, Eun B. Lee, Anamika Ratri, Vishnu Kumar, Courtney A. Marsh, Patrick E. Fields and M. A. Karim Rumi
Cells 2024, 13(7), 644; https://doi.org/10.3390/cells13070644 - 6 Apr 2024
Viewed by 598
Abstract
Increased activation of ovarian primordial follicles in Erβ knockout (ErβKO) rats becomes evident as early as postnatal day 8.5. To identify the ERβ-regulated genes that may control ovarian primordial follicle activation, we analyzed the transcriptome profiles of ErβKO rat [...] Read more.
Increased activation of ovarian primordial follicles in Erβ knockout (ErβKO) rats becomes evident as early as postnatal day 8.5. To identify the ERβ-regulated genes that may control ovarian primordial follicle activation, we analyzed the transcriptome profiles of ErβKO rat ovaries collected on postnatal days 4.5, 6.5, and 8.5. Compared to wildtype ovaries, ErβKO ovaries displayed dramatic downregulation of Indian hedgehog (Ihh) expression. IHH-regulated genes, including Hhip, Gli1, and Ptch1, were also downregulated in ErβKO ovaries. This was associated with a downregulation of steroidogenic enzymes Cyp11a1, Cyp19a1, and Hsd17b1. The expression of Ihh remained very low in ErβKO ovaries despite the high levels of Gdf9 and Bmp15, which are known upregulators of Ihh expression in the granulosa cells of activated ovarian follicles. Strikingly, the downregulation of the Ihh gene in ErβKO ovaries began to disappear on postnatal day 16.5 and recovered on postnatal day 21.5. In rat ovaries, the first wave of primordial follicles is rapidly activated after their formation, whereas the second wave of primordial follicles remains dormant in the ovarian cortex and slowly starts activating after postnatal day 12.5. We localized the expression of Ihh mRNA in postnatal day 8.5 wildtype rat ovaries but not in the age-matched ErβKO ovaries. In postnatal day 21.5 ErβKO rat ovaries, we detected Ihh mRNA mainly in the activated follicles in the ovaries’ peripheral regions. Our findings indicate that the expression of Ihh in the granulosa cells of the activated first wave of ovarian follicles depends on ERβ. Full article
(This article belongs to the Special Issue Hedgehog Signaling: Advances in Development and Cancer)
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Review

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16 pages, 1146 KiB  
Review
Hedgehog Signaling in Cortical Development
by Eva Cai, Maximiliano Gonzalez Barba and Xuecai Ge
Cells 2024, 13(1), 21; https://doi.org/10.3390/cells13010021 (registering DOI) - 21 Dec 2023
Viewed by 1440
Abstract
The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims [...] Read more.
The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex. Full article
(This article belongs to the Special Issue Hedgehog Signaling: Advances in Development and Cancer)
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17 pages, 4535 KiB  
Review
Hedgehog Signaling in Gonadal Development and Function
by Iman Dilower, Asef J. Niloy, Vishnu Kumar, Ayushi Kothari, Eun Bee Lee and M. A. Karim Rumi
Cells 2023, 12(3), 358; https://doi.org/10.3390/cells12030358 - 18 Jan 2023
Cited by 6 | Viewed by 2496
Abstract
Three distinct hedgehog (HH) molecules, (sonic, desert, and indian), two HH receptors (PTCH1 and PTCH2), a membrane bound activator (SMO), and downstream three transcription factors (GLI1, GLI2, and GLI3) are the major components of the HH signaling. These signaling molecules were initially identified [...] Read more.
Three distinct hedgehog (HH) molecules, (sonic, desert, and indian), two HH receptors (PTCH1 and PTCH2), a membrane bound activator (SMO), and downstream three transcription factors (GLI1, GLI2, and GLI3) are the major components of the HH signaling. These signaling molecules were initially identified in Drosophila melanogaster. Later, it has been found that the HH system is highly conserved across species and essential for organogenesis. HH signaling pathways play key roles in the development of the brain, face, skeleton, musculature, lungs, and gastrointestinal tract. While the sonic HH (SHH) pathway plays a major role in the development of the central nervous system, the desert HH (DHH) regulates the development of the gonads, and the indian HH (IHH) acts on the development of bones and joints. There are also overlapping roles among the HH molecules. In addition to the developmental role of HH signaling in embryonic life, the pathways possess vital physiological roles in testes and ovaries during adult life. Disruption of DHH and/or IHH signaling results in ineffective gonadal steroidogenesis and gametogenesis. While DHH regulates the male gonadal functions, ovarian functions are regulated by both DHH and IHH. This review article focuses on the roles of HH signaling in gonadal development and reproductive functions with an emphasis on ovarian functions. We have acknowledged the original research work that initially reported the findings and discussed the subsequent studies that have further analyzed the role of HH signaling in testes and ovaries. Full article
(This article belongs to the Special Issue Hedgehog Signaling: Advances in Development and Cancer)
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27 pages, 1735 KiB  
Review
Establishing Hedgehog Gradients during Neural Development
by Sara Douceau, Tanya Deutsch Guerrero and Julien Ferent
Cells 2023, 12(2), 225; https://doi.org/10.3390/cells12020225 - 5 Jan 2023
Cited by 6 | Viewed by 2836
Abstract
A morphogen is a signaling molecule that induces specific cellular responses depending on its local concentration. The concept of morphogenic gradients has been a central paradigm of developmental biology for decades. Sonic Hedgehog (Shh) is one of the most important morphogens that displays [...] Read more.
A morphogen is a signaling molecule that induces specific cellular responses depending on its local concentration. The concept of morphogenic gradients has been a central paradigm of developmental biology for decades. Sonic Hedgehog (Shh) is one of the most important morphogens that displays pleiotropic functions during embryonic development, ranging from neuronal patterning to axon guidance. It is commonly accepted that Shh is distributed in a gradient in several tissues from different origins during development; however, how these gradients are formed and maintained at the cellular and molecular levels is still the center of a great deal of research. In this review, we first explored all of the different sources of Shh during the development of the nervous system. Then, we detailed how these sources can distribute Shh in the surrounding tissues via a variety of mechanisms. Finally, we addressed how disrupting Shh distribution and gradients can induce severe neurodevelopmental disorders and cancers. Although the concept of gradient has been central in the field of neurodevelopment since the fifties, we also describe how contemporary leading-edge techniques, such as organoids, can revisit this classical model. Full article
(This article belongs to the Special Issue Hedgehog Signaling: Advances in Development and Cancer)
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26 pages, 1608 KiB  
Review
Canonical Hedgehog Pathway and Noncanonical GLI Transcription Factor Activation in Cancer
by Chamey Suchors and James Kim
Cells 2022, 11(16), 2523; https://doi.org/10.3390/cells11162523 - 14 Aug 2022
Cited by 9 | Viewed by 2473
Abstract
The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH [...] Read more.
The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH, as the cause of Basal Cell Nevus Syndrome, which is associated with several cancers. Our understanding of the pathway in tumorigenesis has expanded greatly since that initial discovery over two decades ago. The pathway has tumor-suppressive and oncogenic functions depending on the context of the cancer. Furthermore, noncanonical activation of GLI transcription factors has been reported in a number of tumor types. Here, we review the roles of canonical Hedgehog signaling pathway and noncanonical GLI activation in cancers, particularly epithelial cancers, and discuss an emerging concept of the distinct outcomes that these modes have on cancer initiation and progression. Full article
(This article belongs to the Special Issue Hedgehog Signaling: Advances in Development and Cancer)
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