Regulatory mechanisms of cytoneme-based morphogen transport

Cellular and Molecular Life Sciences (2022) 79:119 https://doi.org/10.1007/s00018-022-04148-x Cellular and Molecular Life Sciences REVIEW Regulatory mechanisms of cytoneme‑based morphogen transport Christina A. Daly1,2 · Eric T. Hall1 · Stacey K. Ogden1 Received: 2 November 2021 / Revised: 5 January 2022 / Accepted: 12 January 2022 © The Author(s) 2022 Abstract During development and tissue homeostasis, cells must communicate with their neighbors to ensure coordinated responses to instructional cues. Cues such as morphogens and growth factors signal at both short and long ranges in temporal- and tissue-specific manners to guide cell fate determination, provide positional information, and to activate growth and survival responses. The precise mechanisms by which such signals traverse the extracellular environment to ensure reliable delivery to their intended cellular targets are not yet clear. One model for how this occurs suggests that specialized filopodia called cytonemes extend between signal-producing and -receiving cells to function as membrane-bound highways along which information flows. A growing body of evidence supports a crucial role for cytonemes in cell-to-cell communication. Despite this, the molecular mechanisms by which cytonemes are initiated, how they grow, and how they deliver specific signals are only starting to be revealed. Herein, we discuss recent advances toward improved understanding of cytoneme biology. We discuss similarities and differences between cytonemes and other types of cellular extensions, summarize what is known about how they originate, and discuss molecular mechanisms by which their activity may be controlled in development and tissue homeostasis. We conclude by highlighting important open questions regarding cytoneme biology, and comment on how a clear understanding of their function may provide opportunities for treating or preventing disease. Keywords HH · WNT · BMP · FGF · Signaling filopodia · Signal transduction Overview Organ and tissue development rely on coordinated dispersal of morphogen signals from cellular organizing centers that provide instructional cues to govern cell fate. Signaling proteins contributing to tissue morphogenesis include Hedgehog (Hh/HH) family members, Transforming Growth Factor-β (TGF- β) and Bone Morphogenic Protein (BMP) family members, WNTs, NOTCH, and members of the Epidermal Growth Factor (EGF) and Fibroblast Growth Factor (FGF) families. These molecules direct distinct transcriptional programs in target cells, oftentimes through concentration- and signal duration-dependent manners [1–5]. * Stacey K. Ogden 1 Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl. MS340, Memphis, TN 38105, USA 2 St. Jude Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl, MS 1500, Memphis, TN 38105, USA Establishment of terminal cell fate across different tissues results from coordinated input from different combinations of morphogen signals. For example, limb development and digit specification are orchestrated through WNT, FGF, BMP, and HH signaling, craniofacial development is instructed primarily by HH and WNT activity [6–8], and pancreatic and endocrine system development are dictated by FGF, BMP, HH, NOTCH, and WNT signals [9]. One of the best examples of the multi-faceted roles of signaling molecules is found in central nervous system (CNS) development. Here, HH, WNT, FGF, and BMP collectively signal to dictate cell fate at early developmental stages and to induce proliferation, promote cell survival, and guide axon pathfinding at later developmental stages [10–22]. A tractable genetic model system in which coordinated developmental signaling can be studied is provided by the Drosophila wing imaginal disc, a sac-like epithelial tissue that is composed of several types of progenitor cells that communicate with one another to drive wing morphogenesis. Epithelial cells of the wing disc signal to a segment of the tracheal system called the Air Sac Primordium (ASP), which develops into the adult dorsal air sacs. Myoblasts found in 13 Vol.:(0123456789) 119 Page 2 of 20 this tissue form the adult flight muscles, which are provided oxygen by the air sacs. For each of these components of the flight system to develop properly, numerous pathways must be induced in precise temporal- and tissue-specific manners. Pathways active during wing cell specification include Hh, the BMP homolog Decapentaplegic (Dpp), FGF homolog Branchless (Bnl), WNT homolog Wingless (Wg), and the NOTCH ligand Delta [23–27]. Dysregulation of any of these pathways during wing morphogenesis results in overt patterning defects that compromise wing development, underscoring the importance of organized multi-pathway input for proper fate determination. In addition to their crucial contributions during development, morphogens also play key roles promoting tissue homeostasis. Morphogens act in the stem cell niche to maintain stemness and promote proliferation or differentiation in response to distinct cues. This is exemplified by maintenance of the intestinal epithelium. Repopulation of cells in the crypts occurs through continuous regeneration from stem cells located at the crypt base. WNT and NOTCH signals maintain the undifferentiated state of cells in the stem cell niche and BMPs promote differentiation of intestinal epithelial cells to replace dying cells in the crypts [28]. Indian Hedgehog (IHH) is expressed by differentiating epithelial cells in the midcrypt region where it signals to the mesenchymal intestinal stem cells (ISCs) [29]. IHH pathway activation indirectly reduces WNT-mediated proliferation, thus stimulating ISC differentiation [29]. Similar mechanisms are found in homeostasis and repair of other adult tissues including the brain, skin, prostate, and bladder [30]. Given the myriad of important functions that depend upon proper activity of these signaling proteins, it is not surprising that their dysregulation can lead to developmental disorders and cancers [31–36]. Despite the importance of controlled signal deployment and delivery for tissue development and homeostasis, the precise mechanisms by which morphogens and growth factors are transported between sending and receiving cells remain a topic of debate. Interest in the mechanisms by which morphogens travel from a signaling source was spurred by discovery of the Spemann–Mangold organizer. This pioneering work demonstrated that specific regions of a developing embryo could influence development of other embryonic regions upon their transplantation [37]. Subsequently, the Dalcq–Pasteels hypothesis suggested that signals emanating from organizing tissues would form a double gradient, with one set of molecules spreading from the vegetal pole of the embryo and a second set simultaneously forming from the dorsal cortex [38]. In 1952, the term “morphogen” was coined to de (...truncated)