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Hedgehog Signaling during Appendage Development and Regeneration.

Singh BN, Koyano-Nakagawa N, Donaldson A, Weaver CV, Garry MG, Garry DJ - Genes (Basel) (2015)

Bottom Line: Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system.Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs.Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms.

View Article: PubMed Central - PubMed

Affiliation: Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA. bnsingh@umn.edu.

ABSTRACT
Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration.

No MeSH data available.


Related in: MedlinePlus

HH signaling and limb development. (A) Schematic outlining the different axises of the developing limb. Limb bud formation is initiated at the defined region of the embryonic axis. The proximal-distal (PD) axis is defined by the direction of the limb outgrowth and the antero-posterior (AP) axis is defined by the sequence of the digits 1 (thumb) to 5 (little finger); (B) In the developing limb bud, an apical ectodermal ridge (AER) is formed at the distal region of the bud. In the AER region, FGF signaling is initiated in a posterior-anterior fashion forming the AER-FGF zone. Retinoic acid (RA) signaling regulates the proximal development of the limb, whereas the distal region (progression zone) is controlled by multiple signaling factors. FGF signaling initiates the HH signaling in the posterior region of the limb bud and the expression of HH signaling is maintained by HOX genes, Tbx and Fgf8 expression. HH signaling inhibits the constitutive processing of Gli3 to its repressor form (Gli3-rep); (C) The posterior region contains high Gli3A and low Gli3-rep and reverse is observed in the anterior region. Following activation, Grem1 (BMP antagonism) functions are required to relay the HH signals to the AER to maintain FGF signaling, thus forming a HH-Grem1-FGF feedback loop in the developing limb bud.
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genes-06-00417-f003: HH signaling and limb development. (A) Schematic outlining the different axises of the developing limb. Limb bud formation is initiated at the defined region of the embryonic axis. The proximal-distal (PD) axis is defined by the direction of the limb outgrowth and the antero-posterior (AP) axis is defined by the sequence of the digits 1 (thumb) to 5 (little finger); (B) In the developing limb bud, an apical ectodermal ridge (AER) is formed at the distal region of the bud. In the AER region, FGF signaling is initiated in a posterior-anterior fashion forming the AER-FGF zone. Retinoic acid (RA) signaling regulates the proximal development of the limb, whereas the distal region (progression zone) is controlled by multiple signaling factors. FGF signaling initiates the HH signaling in the posterior region of the limb bud and the expression of HH signaling is maintained by HOX genes, Tbx and Fgf8 expression. HH signaling inhibits the constitutive processing of Gli3 to its repressor form (Gli3-rep); (C) The posterior region contains high Gli3A and low Gli3-rep and reverse is observed in the anterior region. Following activation, Grem1 (BMP antagonism) functions are required to relay the HH signals to the AER to maintain FGF signaling, thus forming a HH-Grem1-FGF feedback loop in the developing limb bud.

Mentions: The limb bud grows in a proximal-distal (PD) axis and patterning occurs from anterior-posterior (AP) axis (Figure 3A). Multiple reports demonstrated that FGF signaling between the AER and the underlying mesodermal cells function to coordinately generate the PD axis during limb development [41,42,43,44]. Genetic analysis revealed that Fgf8 from the AER and Fgf10 from the underlying mesenchymal cells are essential for limb growth [41,42]. In tetrapods, the development of forelimb and hindlimb position is specified by the T-box factors, Tbx5 and Tbx4. Both forelimb and hindlimb development are regulated by distinct signaling cascades [45,46,47]. For example, the regional expression of Fgf10 is regulated by Wnt2b in the forelimb and by Wnt8c in the hindlimb [48]. In contrast to the PD axis, the AP axis during limb development is modulated by SHH morphogens [41,65]. The expression of SHH is confined to the posterior region of the limb bud and has a graded expression pattern [72,73]. In the anterior region, SHH prevents the processing of Gli3 to form Gli3-rep, which functions as a repressor (Figure 3B) [41,49,64,66,73,74].


Hedgehog Signaling during Appendage Development and Regeneration.

Singh BN, Koyano-Nakagawa N, Donaldson A, Weaver CV, Garry MG, Garry DJ - Genes (Basel) (2015)

HH signaling and limb development. (A) Schematic outlining the different axises of the developing limb. Limb bud formation is initiated at the defined region of the embryonic axis. The proximal-distal (PD) axis is defined by the direction of the limb outgrowth and the antero-posterior (AP) axis is defined by the sequence of the digits 1 (thumb) to 5 (little finger); (B) In the developing limb bud, an apical ectodermal ridge (AER) is formed at the distal region of the bud. In the AER region, FGF signaling is initiated in a posterior-anterior fashion forming the AER-FGF zone. Retinoic acid (RA) signaling regulates the proximal development of the limb, whereas the distal region (progression zone) is controlled by multiple signaling factors. FGF signaling initiates the HH signaling in the posterior region of the limb bud and the expression of HH signaling is maintained by HOX genes, Tbx and Fgf8 expression. HH signaling inhibits the constitutive processing of Gli3 to its repressor form (Gli3-rep); (C) The posterior region contains high Gli3A and low Gli3-rep and reverse is observed in the anterior region. Following activation, Grem1 (BMP antagonism) functions are required to relay the HH signals to the AER to maintain FGF signaling, thus forming a HH-Grem1-FGF feedback loop in the developing limb bud.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488672&req=5

genes-06-00417-f003: HH signaling and limb development. (A) Schematic outlining the different axises of the developing limb. Limb bud formation is initiated at the defined region of the embryonic axis. The proximal-distal (PD) axis is defined by the direction of the limb outgrowth and the antero-posterior (AP) axis is defined by the sequence of the digits 1 (thumb) to 5 (little finger); (B) In the developing limb bud, an apical ectodermal ridge (AER) is formed at the distal region of the bud. In the AER region, FGF signaling is initiated in a posterior-anterior fashion forming the AER-FGF zone. Retinoic acid (RA) signaling regulates the proximal development of the limb, whereas the distal region (progression zone) is controlled by multiple signaling factors. FGF signaling initiates the HH signaling in the posterior region of the limb bud and the expression of HH signaling is maintained by HOX genes, Tbx and Fgf8 expression. HH signaling inhibits the constitutive processing of Gli3 to its repressor form (Gli3-rep); (C) The posterior region contains high Gli3A and low Gli3-rep and reverse is observed in the anterior region. Following activation, Grem1 (BMP antagonism) functions are required to relay the HH signals to the AER to maintain FGF signaling, thus forming a HH-Grem1-FGF feedback loop in the developing limb bud.
Mentions: The limb bud grows in a proximal-distal (PD) axis and patterning occurs from anterior-posterior (AP) axis (Figure 3A). Multiple reports demonstrated that FGF signaling between the AER and the underlying mesodermal cells function to coordinately generate the PD axis during limb development [41,42,43,44]. Genetic analysis revealed that Fgf8 from the AER and Fgf10 from the underlying mesenchymal cells are essential for limb growth [41,42]. In tetrapods, the development of forelimb and hindlimb position is specified by the T-box factors, Tbx5 and Tbx4. Both forelimb and hindlimb development are regulated by distinct signaling cascades [45,46,47]. For example, the regional expression of Fgf10 is regulated by Wnt2b in the forelimb and by Wnt8c in the hindlimb [48]. In contrast to the PD axis, the AP axis during limb development is modulated by SHH morphogens [41,65]. The expression of SHH is confined to the posterior region of the limb bud and has a graded expression pattern [72,73]. In the anterior region, SHH prevents the processing of Gli3 to form Gli3-rep, which functions as a repressor (Figure 3B) [41,49,64,66,73,74].

Bottom Line: Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system.Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs.Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms.

View Article: PubMed Central - PubMed

Affiliation: Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA. bnsingh@umn.edu.

ABSTRACT
Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration.

No MeSH data available.


Related in: MedlinePlus