Apoptotic Cell Death in the Mouse Limb and Its Suppression in the Hammertoe Mutant

Zakeri, Zahra; Quaglino, Daniela; Ahuja, Harleen Singh

doi:10.1006/dbio.1994.1255

Cited by 99 publications

(78 citation statements)

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“…In the mouse mutant Hammertoe, it is striking that, although cell death is decreased in the interdigital regions, digit growth occurs, reaching an equivalent morphology to the one seen at the developmental stage S11 (Zakeri et al, 1994). Similarly, in the null mice for Apaf-1, an evolutionarily conserved gene that codes for a key component of the cell death executing machinery, limbs exhibit a decrease in the number of apoptotic cells in the interdigital tissue and a delay in web elimination, but some degree of digit growth is still noticeable at S11 and could give rise to individualized digits (Cecconi et al, 1998;Yoshida et al, 1998).…”

Section: Digit-interdigit Differential Growthmentioning

confidence: 99%

“…In the chick it first appears in the so-called anterior necrotic zone (ANZ), later in the posterior necrotic zone (PNZ), and in the opaque patch (Hinchliffe and Ede, 1973). In the autopod, massive interdigital tissue cell death has been observed (Saunders et al, 1962), and in the mouse this interdigital cell death shows the typical apoptotic nuclei morphology, DNA ladder by electrophoresis, and cytochemical end-labeling of fragmented DNA, which argues that this PCD is apoptotic (Garcia-Martinez et al, 1993;Zakeri et al, 1993;Zakeri et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Early work from Saunders' group (Saunders et al, 1962), indicated that the PNZ was dispensable for chick limb shaping, since if this tissue is removed before cell death takes place, or if the cell death in this tissue is prevented by insertion of a small piece of central meso-derm, a normal wing is formed. Interdigital cell death has long been proposed to be essential for tissue modeling and for digit separation in amniotes (Gilbert, 1997;van der Hoeven et al, 1994), since massive cell death accompanies the formation of free digits in reptiles , birds (Hinchliffe and Ede, 1973), and mammals (Ballard and Holt, 1968;Zakeri et al, 1994), and interdigital PCD is less abundant in animal species with webbed legs (i.e., duck) (Hurle and Colvee, 1982;Pautou, 1973). 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).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Digit-interdigit Differential Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Salas‐Vidal

Valencia

Covarrubias

2001

Developmental Dynamics

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“…For example, across species, different patterns of cell death in the INZ correlate with different final morphologies of the interdigital region, and INZ inhibition correlates with survival of interdigit webbing (Saunders and Fallon, 1967;Ede, 1967, Hurle andCliment, 1987;Hurle et al, 1996). Within a single species, modifications in the amount of cell death by naturally occurring mutations have been shown to correlate with syndactyly or other modifications in digital pattern Ede, 1967, 1973;Dvorak and Fallon, 1991;van der Hoeven et al, 1994;Zakeri et al, 1994;Aoto et al, 2002). In general, the areas of cell death are considered to play an important function in regulating the quantity of mesenchymal cells and, therefore, the number of digits (Hinchliffe, 1982).…”

Section: Introductionmentioning

confidence: 99%

“…Changes in the number of digits (polydactyly or oligodactyly) are frequent, as well as variable degrees of syndactyly. These malformations are frequently explained by modifications in the proliferation rates and/or cell death (Zakeri et al, 1994;Zou and Niswander, 1996;Sidow et al, 1997;Jiang et al, 1998;Sun et al, 2002;Grotewold and Rü ther, 2002;Francis et al, 2005;Johnson et al, 2005;Lu et al, 2006). Therefore, this study was stimulated by the need for a comprehensive description of the spatial and temporal distribution of cell death and cell proliferation during limb development.…”

Section: Introductionmentioning

confidence: 99%

Birth and death of cells in limb development: A mapping study

Fernandez-Teran¹,

Hinchliffe²,

Ros³

2006

Developmental Dynamics

114

104

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Cell death and cell proliferation are basic cellular processes that need to be precisely controlled during embryonic development. The developing vertebrate limb illustrates particularly well how correct morphogenesis depends on the appropriate spatial and temporal balance between cell death and cell proliferation. Precise knowledge of the patterns of cell proliferation and cell death during limb development is required to understand how their modifications may contribute to the generation of the great diversity of limb phenotypes that result from spontaneous mutations or induced genetic manipulations. We have performed a comprehensive analysis of the patterns of cell death, assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling (TUNEL), and cell proliferation, assayed by anti-phosphorylated histone H3 immunohistochemistry, in consecutive sections of forelimbs and hindlimbs covering an extensive period of chick and mouse limb development. Our results confirm and expand previous reports and show common and specific areas of cell death for each species. Mitotic cells were found scattered in a uniform distribution across the early limb bud, with the exception of the areas of cell death in which mitotic cells were scarce. At later stages, mitotic cells were seen more abundantly in the digital tips. The aim of the present study was to satisfy the need for organized data sets describing these processes, which will allow the side-by-side comparison between the two major model organisms of limb development, i.e., the mouse and the chick.

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Induction of thermotolerance in early postimplantation rat embryos is associated with increased resistance to hyperthermia-induced apoptosis

et al. 1997

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Apoptotic Cell Death in the Mouse Limb and Its Suppression in the Hammertoe Mutant

Cited by 99 publications

References 0 publications

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

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

Birth and death of cells in limb development: A mapping study

Induction of thermotolerance in early postimplantation rat embryos is associated with increased resistance to hyperthermia-induced apoptosis

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