Faculty Opinions recommendation of The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells.

We have determined that Strong's Luxoid (lstJ) [corrected] mice have a 16 bp deletion in the homeobox region of the Alx-4 gene. This deletion, which leads to a frame shift and a truncation of the Alx-4 protein, could cause the polydactyly phenotype observed in lstJ [corrected] mice. We have cloned the chick homologue of Alx-4 and investigated its expression during limb outgrowth. Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud. Local application of Sonic hedgehog (Shh) and Fibroblast Growth Factor (FGF), in addition to ectodermal apical ridge removal experiments suggest the existence of a negative feedback loop between Alx-4 and Shh during limb outgrowth. Analysis of polydactylous mutants indicate that the interaction between Alx-4 and Shh is independent of Gli3, a negative regulator of Shh in the limb. Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth.

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Faculty Opinions recommendation of The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020142.242464 ◽

2004 ◽

Author(s):

Alexandra Joyner

Keyword(s):

Feedback Loop ◽

Limb Bud

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Activation of the WNT-BMP-FGF Regulatory Network Induces the Onset of Cell Death in Anterior Mesodermal Cells to Establish the ANZ

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.703836 ◽

2021 ◽

Vol 9 ◽

Author(s):

Martha Elena Díaz-Hernández ◽

Claudio Iván Galván-Hernández ◽

Jessica Cristina Marín-Llera ◽

Karen Camargo-Sosa ◽

Marcia Bustamante ◽

...

Keyword(s):

Cell Death ◽

Wnt Signaling ◽

Regulatory Network ◽

Feedback Loop ◽

Anterior Margin ◽

Bmp Signaling ◽

Limb Bud ◽

Digit Number ◽

Spatiotemporal Control ◽

Signaling Interactions

The spatiotemporal control of programmed cell death (PCD) plays a significant role in sculpting the limb. In the early avian limb bud, the anterior necrotic zone (ANZ) and the posterior necrotic zone are two cell death regions associated with digit number reduction. In this study, we evaluated the first events triggered by the FGF, BMP, and WNT signaling interactions to initiate cell death in the anterior margin of the limb to establish the ANZ. This study demonstrates that in a period of two to 8 h after the inhibition of WNT or FGF signaling or the activation of BMP signaling, cell death was induced in the anterior margin of the limb concomitantly with the regulation of Dkk, Fgf8, and Bmp4 expression. Comparing the gene expression profile between the ANZ and the undifferentiated zone at 22HH and 25HH and between the ANZ of 22HH and 25HH stages correlates with functional programs controlled by the regulatory network FGF, BMP, and WNT signaling in the anterior margin of the limb. This work provides novel insights to recognize a negative feedback loop between FGF8, BMP4, and DKK to control the onset of cell death in the anterior margin of the limb to the establishment of the ANZ.

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