Detailed lines of work >Limb development as a model of tissue growth and patterning, and cell differentiation

In our laboratory, we use the vertebrate limb bud as an experimental model to study the cellular and molecular mechanisms that regulate pattern formation during embryogenesis. Vertebrate limbs perform crucial roles, being involved in locomotion, feeding, copulation, communication, and other complex tasks.

Over the years, classical embryological studies in avian and amphibian embryos, combined with essays of ectopic expression in the chick and gene knock-outs in mouse, have greatly contributed to our understanding of how growth and patterning are integrated in the limb bud. From these and other studies, it is clear that many mechanisms that regulate growth and patterning in the limb bud are also used in many other embryonic structures and organs throughout embryonic development. A synthesis of embryological, cellular, molecular and evolutionary approaches to the study of limb development in different organisms has provided very useful insights into a variety of patterning mechanisms that appear to be conserved during evolution. The limb primordium (the limb bud) appears at specific locations in the developing embryo (Figure 1A), positioned by combinations of factors that provide positional cues. Later the limb bud, constituted by mesenchymal cells covered by ectoderm, starts growing out of the body wall, and specific epithelial-mesenchymal interactions are established that coordinate growth and patterning through the activities of specialized regions of the limb bud that act as organizers (Figure 1B). This basic mechanism, which operates (with some variations) in most tetrapods, results in the development of a variety of adult vertebrate limbs which, despite their varied morphologies and functionalities, share a common morphologic plan (Figure 1C).


Figure 1A: The basic structures of the limb bud and the adult limb are conserved among vertebrates. Vertebrate limbs originate as two pairs of primordia (limb buds) that appear at specific levels of the embryonic flank (forelimb and hindlimb buds are indicated in a chick embryo). View [+]

Figure 1B: The basic structures of the limb bud and the adult limb are conserved among vertebrates. The limb primordium (limb bud) is composed of mesenchymal cells encased in an ectodermal jacket, and contains specific regions that pattern the bud along the anterior-posterior (AP), dorsal-ventral (DV) and proximal-distal (PD) axes. The ZPA (zone of polarizing activity) patterns the AP axis, the AER (apical ectodermal ridge) maintains outgrowth of the limb bud, keeping underlying mesenchimal cells in the PZ (progress zone) in an undifferentiated state. Not shown, the dorsal and ventral ectoderm determine the DV polarity of the distal part of the limb. View [+]

Figure 1C: The basic structures of the limb bud and the adult limb are conserved among vertebrates. Schematic representations of the skeletal structure of forelimbs from several vertebrates, as indicated. The basic skeletal structure of the vertebrate limb is remarkably conserved among amniote tetrapods, consisting of a proximal part (stylopod, in black) with a single skeletal element, a medial part (zeugopod, in gray) with two elements, and a distal part (autopod, in white) composed of carpus or tarsus and a variable number of radiating digits. Despite this general conservation, there is a great morphological and functional diversity, most likely derived from variations in the molecular mechanisms that sculpt the limb, some of which are already known. View [+]

Figure 2A: Territories in the limb bud defined by restricted patterns of gene expression. hx2b expression in the anterior mesenchyme of a stage 24 forelimb bud. View [+]

Figure 2B: Territories in the limb bud defined by restricted patterns of gene expression. Expression of Fgf-8 in the AER of a stage 23 forelimb bud. View [+]

Figure 2C: Territories in the limb bud defined by restricted patterns of gene expression. Lmx-1 expression in the dorsal mesenchyme of a stage 23 forelimb bud. View [+]

Figure 2D: Territories in the limb bud defined by restricted patterns of gene expression. Meis expression in the proximal part of a stage 20 hindlimb bud. View [+]


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