Requirement for BMP Signaling in Interdigital Apoptosis and Scale Formation

Zou, Hongyan; Niswander, Lee

doi:10.1126/science.272.5262.738

Cited by 514 publications

(385 citation statements)

References 28 publications

(9 reference statements)

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“…Indeed, known genes activated in response to BMP-4 signaling were largely transcribed. Among them, the transcriptional regulator Msx-2 has been reported as a BMP target gene in apoptosis of rhombencephalic neural crest cells, 12 chick limb, 14,35 calvarial bone 36 and other tissues. 37 The nature of the genes activated by Msx-2 expression and leading to apoptosis are not yet defined.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 In particular, BMP-4 triggers apoptosis in prospective neural crest cells, 12 in the dorsal portion of the chick optic cup during morphogenesis of the eye 13 and in the interdigital space of the developing limbs in birds. 14 Similarly, BMP responses lead to apoptosis of committed populations of neural stem cells isolated from progressively older fetuses, and then to neuronal and finally glial differentiation. 15,16 We recently reported the ability of BMP-4 to efficiently promote murine ES cell differentiation towards epidermal fate and skin organogenesis in vitro.…”

Section: Introductionmentioning

confidence: 99%

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BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

et al. 2005

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Embryonic ectoderm is fated to become either neural or epidermal, depending on patterning processes that occur before and during gastrulation. It has been stated that epidermal commitment proceeds from a bone morphogenetic protein-4 (BMP-4)-dependent inhibition of dorsal ectoderm neuralization. We recently demonstrated that murine embryonic stem (ES) cells treated with BMP-4 undergo effective keratinocyte commitment and epidermogenesis. Focusing on the precise role of BMP-4 in the early choice between neural and epidermal commitment, we show here that BMP-4 treatment of ES cells leads to a dramatic apoptotic death of Sox-1 þ neural precursors with concomitant epidermal engagement. In addition, neutralization of the Smad pathway prevents both the BMP-4 apoptotic process and the inhibition of neural differentiation. Our results suggest that, in mammals, BMP-4, as an active inducer of epidermal commitment, interferes with the survival of neural precursors through induction of their apoptotic cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

et al. 2005

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“…Subordinate genes include wingless and decapentaplegic (dpp), which code for signaling molecules of the Wnt and TGFb families, respectively. Furthermore the human homologue of dpp was identi®ed as bone morphogenetic factor 4 (BMP-4) a signaling molecule shown to be required for interdigital apoptosis within the developing chick limb (Zou and Niswander, 1996). Pbx has also been implicated as a cofactor with the non-Hox homeodomain protein STF-1 in the regulation of somatostatin gene expression (Peers et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

et al. 1997

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The chimeric oncoprotein E2a-Pbx1 results from fusion of the E2A and PBX1 genes following t(1;19) chromosomal translocations in B cell precursor acute leukemias. Experimentally B cell progenitors do not tolerate constitutive expression of E2a-Pbx1 which contrasts with transformation of several other cell types following its stable expression both in vitro and in vivo. To further investigate the e ects of E2a-Pbx1 on the B cell progenitors, we conditionally expressed E2a-Pbx1 under control of a metal response element in hematopoietic precursor cell lines in vitro. Inducible expression of E2a-Pbx1 resulted in cell death with the morphologic and molecular features of apoptosis. A structure-function analysis demonstrated that induction of apoptosis was not a dominant-negative e ect of the E2a moiety but, rather, required the DNA-binding homeodomain of Pbx1. E2a-Pbx1-induced apoptosis proceeded through a BCL2-responsive checkpoint eventuating in PARP inactivation but did require p53. Constitutive expression of E2a-Pbx1 did not induce apoptosis or continued cycling of Rat-1 ®broblasts in low serum conditions. These studies demonstrate that E2a-Pbx1 initiates programmed cell death of hematopoietic precursers by a mechanism that requires its chimeric transcriptional properties, but, unlike other nuclear oncoproteins, is independent of p53.

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“…In some cases, these proposals have been supported by experimental evidence as in the case of BMP's (Yokouchi et al, 1996;Zou and Niswander, 1996) and retinoic acid receptors (Lohnes et al, 1994). To test if the reported gene expression patterns relate directly to the areas of cell death and tissue growth, we superimposed the images of expression patterns by using the method described above.…”

Section: Gene Expression During Interdigital Cell Deathmentioning

confidence: 92%

“…For example, in the developing chick limb, it has been previously proposed that interdigit degeneration is coincident with digit elongation, resulting in the individualization of digits (Saunders et al, 1962). Furthermore, blockade of BMP signaling has resulted in webbed limbs by apparently preventing cell death (Yokouchi et al, 1996;Zou and Niswander, 1996).…”

Section: Introductionmentioning

confidence: 99%

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

Salas‐Vidal

Valencia

Covarrubias

2001

Developmental Dynamics

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Programmed cell death (PCD) is considered one of the most important cellular processes in the morphogenesis of organs and tissues during animal development. Although the embryonic limb has been established as a classic model for the study of PCD, detailed studies on this process' contribution to morphogenesis are still lacking. In the present work, using modern computer-aided techniques, we estimated the contribution of PCD to mouse limb morphogenesis. For the detection of apoptotic cell death, we stained whole embryonic limbs with acridine orange or, in some instances, used the TUNEL technique, and visualized the tissues by confocal laser scanning microscopy. We found that cell death patterns are dynamic during limb development, and occur in gradients oriented with the main limb axes, anteroposterior, dorsoventral and distoproximal. Interdigital apoptosis in the autopod was initially detected at the most distal region, and then more proximally as development proceeded. Interestingly, we found that digit separation is more pronounced on the dorsal side, contrary to what is expected from the apoptotic cell distribution, which shows more abundant cell death in the ventral region. Using 2-D and 3-D models, we found that most digit individualization occurs rather by digit growth than by interdigital cell death. Therefore, digits do not mainly individualize by degeneration of preformed interdigital tissue, but probably by a dynamic balance between proliferation and cell death, reducing interdigital growth, which results in protrusion of digits. We determined the expression pattern of fgf-8 during the period of digit individualization, as the product of this gene could participate in defining the limb growth pattern. Initially, fgf-8 expression was coincident with the apical ectodermal ridge, but when cell death was first detected in the interdigits, fgf-8 expression became restricted to the tip of the growing digits. Therefore, FGF-8 could be one of the factors responsible for differential digit-interdigit growth, and might also act as a survival factor on interdigital tissue. We also found that the expression patterns of rar-␤, bmp-2, bmp-4, bmp-7, msx-1, and msx-2 genes, proposed to be involved in the activation of interdigital cell death, did not overlap with, or were not highly expressed in the major zones of cell death in the developing limb.

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Requirement for BMP Signaling in Interdigital Apoptosis and Scale Formation

Cited by 514 publications

References 28 publications

BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

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