Hedgehog Signal and Genetic Disorders

Abstract

The hedgehog (Hh) family comprises sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh), which are versatile signaling molecules involved in a wide spectrum of biological events including cell differentiation, proliferation, and survival; establishment of the vertebrate body plan; and aging. These molecules play critical roles from embryogenesis to adult stages; therefore, alterations such as abnormal expression or mutations of the genes involved and their downstream factors cause a variety of genetic disorders at different stages. The Hh family involves many signaling mediators and functions through complex mechanisms, and achieving a comprehensive understanding of the entire signaling system is challenging. This review discusses the signaling mediators of the Hh pathway and their functions at the cellular and organismal levels. We first focus on the roles of Hh signaling mediators in signal transduction at the cellular level and the networks formed by these factors. Then, we analyze the spatiotemporal pattern of expression of Hh pathway molecules in tissues and organs, and describe the phenotypes of mutant mice. Finally, we discuss the genetic disorders caused by malfunction of Hh signaling-related molecules in humans.

Sonic Hedgehog Signaling Agonist (SAG) Triggers BDNF Secretion and Promotes the Maturation of GABAergic Networks in the Postnatal Rat Hippocampus

“…Shh is a prominent neurotrophic factor that acts at multiple levels during central nervous system development from embryonic through postnatal stages, and perturbations in its activity lead to major neurodevelopmental disorders (Currier et al, 2012;Boyd et al, 2015;Halepoto et al, 2015;Feng et al, 2016;Patel et al, 2017;Kumar et al, 2019;Sasai et al, 2019). Here, we demonstrate in both hippocampal slices and neuronal cultures that the Smo agonist SAG modulates spontaneous network activity and GABAergic synaptic plasticity in the maturing rodent hippocampus through the secretion and signaling of BDNF and an intracellular Ca 2+ -dependent mechanism.…”

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

“…The Hedgehog (Hh), secreted glycoproteins, was first identified as a critical mediator of precise pattern formation during embryo development, and it is also involved in the regulation of growth, cell migration, and differentiation [ 197 , 198 , 199 ]. In mammals, Hh signaling is comprise of three known ligands, Sonic hedgehog (Shh), Desert hedgehog (Dhh), and Indian hedgehog (Ihh) [ 200 ]. Inappropriate activation of the Hh signaling has been described in a variety of human cancers including pancreatic, skin, and gastrointestinal cancers [ 201 , 202 ].…”

Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

“…Hedgehog (Hh) signaling, well-known as a mitogen and morphogen during animal development, also regulates adult tissue homeostasis and tumorigenesis [1][2][3][4]. Hh ligands in mammals are three proteins, Indian hedgehog (Ihh), Sonic hedgehog, and Desert hedgehog; although they are expressed in different cells and tissues, their functions are not considered different [5,6]. Hh ligands bind to and inhibit main receptor Patched-1 (PTCH1, encoded by the Ptch1 gene), permitting the activation of Hh signal transducer smoothened (SMO, encoded by the Smo gene) and transmitting intracellular signaling through transcription factors of the GLI family [5,7,8].…”