Journal of Developmental Biology

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Open AccessReview

Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What is the Role of Competence?

by Clemens Kiecker, Anthony Graham and Malcolm Logan

J. Dev. Biol. 2016, 4(4), 36; https://doi.org/10.3390/jdb4040036 - 10 Dec 2016

Cited by 6 | Viewed by 6753

A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to [...] Read more.

A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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Open AccessReview

The Many Hats of Sonic Hedgehog Signaling in Nervous System Development and Disease

by Yesser H. Belgacem, Andrew M. Hamilton, Sangwoo Shim, Kira A. Spencer and Laura N. Borodinsky

J. Dev. Biol. 2016, 4(4), 35; https://doi.org/10.3390/jdb4040035 - 10 Dec 2016

Cited by 41 | Viewed by 10917

Abstract

Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding [...] Read more.

Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding and synapse formation and function. To participate in these diverse events, Shh signaling manifests differently depending on the maturational state of the responsive cell, on the other signaling pathways regulating neural cell function and the environmental cues that surround target cells. Shh signaling is particularly dynamic in the nervous system, ranging from canonical transcription-dependent, to non-canonical and localized to axonal growth cones. Here, we review the variety of Shh functions in the developing nervous system and their consequences for neurodevelopmental diseases and neural regeneration, with particular emphasis on the signaling mechanisms underlying Shh action. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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1361 KiB

Open AccessReview

Perspectives on Intra- and Intercellular Trafficking of Hedgehog for Tissue Patterning

by Eléanor Simon, Adrián Aguirre-Tamaral, Gustavo Aguilar and Isabel Guerrero

J. Dev. Biol. 2016, 4(4), 34; https://doi.org/10.3390/jdb4040034 - 02 Dec 2016

Cited by 10 | Viewed by 6852

Abstract

Intercellular communication is a fundamental process for correct tissue development. The mechanism of this process involves, among other things, the production and secretion of signaling molecules by specialized cell types and the capability of these signals to reach the target cells in order [...] Read more.

Intercellular communication is a fundamental process for correct tissue development. The mechanism of this process involves, among other things, the production and secretion of signaling molecules by specialized cell types and the capability of these signals to reach the target cells in order to trigger specific responses. Hedgehog (Hh) is one of the best-studied signaling pathways because of its importance during morphogenesis in many organisms. The Hh protein acts as a morphogen, activating its targets at a distance in a concentration-dependent manner. Post-translational modifications of Hh lead to a molecule covalently bond to two lipid moieties. These lipid modifications confer Hh high affinity to lipidic membranes, and intense studies have been carried out to explain its release into the extracellular matrix. This work reviews Hh molecule maturation, the intracellular recycling needed for its secretion and the proposed carriers to explain Hh transportation to the receiving cells. Special focus is placed on the role of specialized filopodia, also named cytonemes, in morphogen transport and gradient formation. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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Open AccessReview

Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications

by Cândida Lucas, Célia Ferreira, Giulia Cazzanelli, Ricardo Franco-Duarte and Joana Tulha

J. Dev. Biol. 2016, 4(4), 33; https://doi.org/10.3390/jdb4040033 - 05 Nov 2016

Cited by 5 | Viewed by 7885

Abstract

In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to [...] Read more.

In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to their secretion, while HHATL (Hh O-acyltransferase-like) negatively regulates the pathway. HHAT and HHATL are homologous to Saccharomyces cerevisiae Gup2 and Gup1, respectively. In yeast, Gup1 is associated with a high number and diversity of biological functions, namely polarity establishment, secretory/endocytic pathway functionality, vacuole morphology and wall and membrane composition, structure and maintenance. Phenotypes underlying death, morphogenesis and differentiation are also included. Paracrine signalling, like the one promoted by the Hh pathway, has not been shown to occur in microbial communities, despite the fact that large aggregates of cells like biofilms or colonies behave as proto-tissues. Instead, these have been suggested to sense the population density through the secretion of quorum-sensing chemicals. This review focuses on Gup1/HHATL and Gup2/HHAT proteins. We review the functions and physiology associated with these proteins in yeasts and higher eukaryotes. We suggest standardisation of the presently chaotic Gup-related nomenclature, which includes KIAA117, c3orf3, RASP, Skinny, Sightless and Central Missing, in order to avoid the disclosure of otherwise unnoticed information. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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Open AccessArticle

Asxl2^−/− Mice Exhibit De Novo Cardiomyocyte Production during Adulthood

by Rachel Brunner, Hsiao-Lei Lai, Zane Deliu, Elan Melman, David L. Geenen and Q. Tian Wang

J. Dev. Biol. 2016, 4(4), 32; https://doi.org/10.3390/jdb4040032 - 03 Nov 2016

Cited by 3 | Viewed by 6453

Abstract

Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, [...] Read more.

Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2^−/− heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin⁺ non-cardiomyocytes in Asxl2^−/− over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the Asxl2^−/− heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2^−/− hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2^−/− heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity. Full article

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Open AccessReview

An Evolutionarily Conserved Network Mediates Development of the zona limitans intrathalamica, a Sonic Hedgehog-Secreting Caudal Forebrain Signaling Center

by Elena Sena, Kerstin Feistel and Béatrice C. Durand

J. Dev. Biol. 2016, 4(4), 31; https://doi.org/10.3390/jdb4040031 - 20 Oct 2016

Cited by 8 | Viewed by 6405

Abstract

Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only [...] Read more.

Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh) whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN). Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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8081 KiB

Open AccessReview

Hedgehog Signaling in Prostate Development, Regeneration and Cancer

by Wade Bushman

J. Dev. Biol. 2016, 4(4), 30; https://doi.org/10.3390/jdb4040030 - 19 Oct 2016

Cited by 17 | Viewed by 5452

Abstract

The prostate is a developmental model system study of prostate growth regulation. Historically the research focus was on androgen regulation of development and growth and instructive interactions between the mesenchyme and epithelium. The study of Hh signaling in prostate development revealed important roles [...] Read more.

The prostate is a developmental model system study of prostate growth regulation. Historically the research focus was on androgen regulation of development and growth and instructive interactions between the mesenchyme and epithelium. The study of Hh signaling in prostate development revealed important roles in ductal morphogenesis and in epithelial growth regulation that appear to be recapitulated in prostate cancer. This overview of Hh signaling in the prostate will address the well-described role of paracrine signaling prostate development as well as new evidence suggesting a role for autocrine signaling, the role of Hh signaling in prostate regeneration and reiterative activities in prostate cancer. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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6285 KiB

Open AccessArticle

Loss of Suppressor of Fused in Mid-Corticogenesis Leads to the Expansion of Intermediate Progenitors

by Odessa R. Yabut, Hui Xuan Ng, Gloria Fernandez, Keejung Yoon, Jeremy Kuhn and Samuel J. Pleasure

J. Dev. Biol. 2016, 4(4), 29; https://doi.org/10.3390/jdb4040029 - 29 Sep 2016

Cited by 5 | Viewed by 5714

Abstract

Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates [...] Read more.

Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates the proliferation of intermediate progenitor (IP) cells at later stages of corticogenesis to affect the number of Cux1+ upper layer neurons in the postnatal neocortex. This correlates with abnormal levels of the repressor form of Gli3 (Gli3R) and the ectopic expression of Patched 1 (Ptch1), a Sonic Hedgehog (Shh) target gene. These studies reveal that the canonical role of Sufu as an inhibitor of Shh signaling is conserved at later stages of corticogenesis and that Sufu plays a crucial role in regulating neuronal number by controlling the cell cycle dynamics of IP cells in the embryonic neocortex. Full article

(This article belongs to the Collection Hedgehog Signaling in Embryogenesis)

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J. Dev. Biol., Volume 4, Issue 4 (December 2016) – 8 articles

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