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    • br Hh Proteins at a Glance Hh family

    2021-11-25


    Hh Proteins at a Glance Hh family proteins are evolutionarily conserved morphogens that provide cells with positional information and fate instruction during early embryonic development. After development, Hh ligands contribute to tissue homeostasis and wound healing 1., 2.. Consistent with these roles, developmental pathologies such as holoprosencephaly (HPE) (see Glossary) (Box 1) and Pallister Hall syndrome, and cancers including medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, can result from Hh pathway dysregulation 3., 4., 5.. Thus, a clear understanding of the molecular mechanisms driving the release, delivery, and interpretation of the Hh signal in both physiological and pathophysiological contexts is essential. The Hh gene was discovered in Drosophila melanogaster through a genetic screen aimed at identifying drivers of embryonic patterning [6]. Subsequent studies revealed vertebrates to have three Hh protein orthologs, referred to as Sonic Hh (Shh), Desert Hh, and Indian Hh [7]. For the purposes of this review, we refer to the Drosophila ligand as Hh, use Shh when discussing studies involving vertebrate Hh proteins, and Hedgehogs (Hhs) when referring to ligand release or transport processes shared by all Hh family members. A unique aspect of Hhs that influences their cellular release and activity is that they are dually lipid modified by a long-chain fatty amc 7 on the amino terminus and by a covalently linked cholesterol moiety at the carboxyl terminus 8., 9.. These hydrophobic lipid modifications behave as lipid anchors that tether Hhs to producing cell membranes. Because Hhs must signal to target cells that can be situated up to ~300 μm from their site of production in vertebrates and ~50 μm in flies, cellular machinery capable of alleviating the lipid anchors is necessary 10., 11.. A crucial component of this machinery is the transporter-like protein Disp, which is an evolutionarily conserved pathway regulator that was first identified in Drosophila nearly 20 years ago [12]. The importance of Disp for Hhs deployment and morphogen gradient formation is supported by multiple genetic studies in both flies and vertebrates 12., 13., 14., 15., 16.. However, until recently the molecular mechanisms controlling Disp activity and facilitating the release of Hhs from producing cell membranes have remained unclear. A number of recent biochemical analyses of Disp, combined with cryogenic electron microscopy (cryo-EM) studies of the structurally homologous Shh receptor Patched (Ptch), have begun to shed light on cellular processes that can impact Disp regulation and function. Herein we review these studies to summarize current understanding of how Disp facilitates the release and distribution of Hh family members.
    Disp Shapes the Hhs Morphogen Gradient Cholesterol modification of Hh ligands is essential for the establishment of their morphogen gradients, which provide both short- and long-range signals across developing tissues 17., 18., 19.. Hhs lacking cholesterol are secreted from producing cells in an unregulated manner, leading to inappropriate distribution across target fields of cells [17]. The direct mechanism by which cholesterol contributes to Hhs morphogen gradients is unclear, but it is well established that cholesterol-modified Hhs require Disp to deploy for long-range signaling. In the absence of Disp function, Hhs fail to release from signal-producing cells and the morphogen gradients collapse (Box 2) 12., 13.. Juxtacrine signaling to cells directly adjacent to a Hhs source can be maintained without Disp, but long-range targets do not receive ligand. Thus, cells situated far from the morphogen source fail to adopt appropriate fates, which corrupts tissue patterning and leads to early embryonic lethality. Disp-knockout mice show overt left/right asymmetry defects and die around ~E9.5 12., 13., 14., 15.. These mice phenocopy animals lacking the Hh pathway signal transducing protein Smoothened (Smo), underscoring the importance of Disp for Shh pathway activity during early development.