Hedgehog Morphogens Act as Growth Factors Critical to Pre- and Postnatal Cardiac Development and Maturation: How Primary Cilia Mediate Their Signal Transduction

Abstract

Primary cilia are crucial for normal cardiac organogenesis via the formation of cyto-architectural, anatomical, and physiological boundaries in the developing heart and outflow tract. These tiny, plasma membrane-bound organelles function in a sensory-integrative capacity, interpreting both the intra- and extra-cellular environments and directing changes in gene expression responses to promote, prevent, and modify cellular proliferation and differentiation. One distinct feature of this organelle is its involvement in the propagation of a variety of signaling cascades, most notably, the Hedgehog cascade. Three ligands, Sonic, Indian, and Desert hedgehog, function as growth factors that are most commonly dependent on the presence of intact primary cilia, where the Hedgehog receptors Patched-1 and Smoothened localize directly within or at the base of the ciliary axoneme. Hedgehog signaling functions to mediate many cell behaviors that are critical for normal embryonic tissue/organ development. However, inappropriate activation and/or upregulation of Hedgehog signaling in postnatal and adult tissue is known to initiate oncogenesis, as well as the pathogenesis of other diseases. The focus of this review is to provide an overview describing the role of Hedgehog signaling and its dependence upon the primary cilium in the cell types that are most essential for mammalian heart development. We outline the breadth of developmental defects and the consequential pathologies resulting from inappropriate changes to Hedgehog signaling, as it pertains to congenital heart disease and general cardiac pathophysiology.

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…Primary cilia are often considered to act as antennae, an integral part of its cell's sensory apparatus [59][60][61] . Therefore, after establishing that nociceptors express primary cilia, we tested the hypothesis that they are involved in the transduction of noxious stimuli and contribute to nociceptor sensitization in inflammatory and neuropathic pain.…”

Differentiation of Pluripotent Stem Cells for Disease Modeling: Learning from Heart Development

“…The hedgehog (Hh) signaling pathway can regulate many cell behaviors during embrogenesis [ 114 ]. Hedgehog signaling is initiated by the binding of the Hh ligands Sonic hedgehog (Shh), Indian hedgehog (Ihh), or Desert hedgehog (Dhh) to their cell surface receptors Patched1 (PTCH1) or Patched2 (PTCH2).…”

Functions of actin‐binding proteins in cilia structure remodeling and signaling

“…The Hh signaling pathway is associated with embryonic tissue and organ development and many kinds of cancers (Doheny et al., 2020, Fitzsimons et al., 2022). In the Hh signaling pathway, Ptch receptors inhibit the activity of Smo without activation by Hh ligands, but in the presence of Hh ligands that bind Ptch receptors, Smo is inactivated.…”