Circumventing the polydactyly 'constraint': the mole's 'thumb'.

Talpid moles across all northern continents exhibit a remarkably large, sickle-like radial sesamoid bone anterior to their five digits, always coupled with a smaller tibial sesamoid bone. A possible developmental mechanism behind this phenomenon was revealed using molecular markers during limb development in the Iberian mole (Talpa occidentalis) and a shrew (Cryptotis parva), as shrews represent the closest relatives of moles but do not show these conspicuous elements. The mole's radial sesamoid develops later than true digits, as shown by Sox9, and extends into the digit area, developing in relation to an Msx2-domain at the anterior border of the digital plate. Fgf8 expression, marking the apical ectodermal ridge, is comparable in both species. Developmental peculiarities facilitated the inclusion of the mole's radial sesamoid into the digit series; talpid moles circumvent the almost universal pentadactyly constraint by recruiting wrist sesamoids into their digital region using a novel developmental pathway and timing.

Hox11 paralogous genes are required for formation of wrist and ankle joints and articular surface organization.

Limb skeletal elements are connected by distinct synovial joints, but the mechanisms regulating joint formation, diversity, and organization remain unclear. Previous studies showed that Hox11 mouse mutants have severe developmental defects in radius and ulna and tibia and fibula, but wrist and ankle joint formation and characteristics were not examined in detail. We now find that E11.5 and E12.5 triple Hox11aaccdd mutants exhibit a significant reduction in prospective carpal and tarsal mesenchyme. Although the mesenchyme became segmented into individual carpal and tarsal skeletal elements with further development, the elements were ill defined and the more proximal elements (radiale, ulnare, talus, and calcaneous) actually underwent involution and/or fusion. Wild-type carpal and tarsal elements displayed a thick articulating superficial zone at their outer perimeter that expressed genes typical of developing joint interzones and articulating cells, including Gdf5, Erg, Gli3, collagen IIA, and lubricin, and defined each element anatomically. In mutant wrists and ankles, the superficial zone around each element was thin and ill defined, and expression of several of those genes was low and often interrupted. These and other data provide novel and clear evidence that Hox11 paralogous genes regulate wrist and ankle joint organization and are essential for establishing carpal and tarsal element boundary and maintaining their articulating surface tissue.

Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb.

The vertebrate forelimb and hindlimb are serially homologous structures; however, their distinctive morphologies suggest that different mechanisms are associated with each limb type to give rise to limb-type identity. Three genes have been implicated in this process; T-box transcription factors Tbx5 and Tbx4, which are expressed in the forelimb and hindlimb, respectively, and a paired-type homeodomain transcription factor Pitx1, expressed in the hindlimb. To explore the roles of Pitx1 and Tbx4 in patterning the hindlimb, we have ectopically misexpressed these genes in the mouse forelimb using transgenic methods. We have developed a novel technique for visualising the structure and organisation of tissues in limbs in 3D using optical projection tomography (OPT). This approach provides unparalleled access to understanding the relationships between connective tissues during development of the limb. Misexpression of Pitx1 in the forelimb results in the transformation and translocation of specific muscles, tendons, and bones of the forelimb so that they acquire a hindlimb-like morphology. Pitx1 also upregulates hindlimb-specific factors in the forelimb, including Hoxc10 and Tbx4. In contrast, misexpression of Tbx4 in the forelimb does not result in a transformation of limb-type morphology. These results demonstrate that Pitx1, but not Tbx4, determines the morphological identity of hindlimb tissues.

The mole's thumb -- evolution of the hand skeleton in talpids (Mammalia).

Osteological specimens representing 15 out of the 16 currently recognized talpid genera were examined and scored for seven discrete morphological characters of the hand. The phylogenetic distribution of these characters was studied in the context of alternative hypotheses of talpid relationships, using three species of shrews and a hedgehog as outgroups. All talpids show a similar number and arrangement of carpal bones. The most obvious differences concern the presence of additional sesamoid bones, the relative size of the os falciforme when present, and the degree of fusion of the scaphoid and lunate in the proximal carpal row. Marked differences in the relative length and proportions of the metacarpals also exist. The development of the carpals in Talpa europaea was studied through examination of histological sections of the hand of an embryo and a neonate. Whereas carpal anatomy in the neonate mirrors the arrangement and proportions of the adult, in the embryo the scaphoid and lunate are still separate, there are no signs of the os falciforme, and the size proportions of metacarpals to carpals are obviously different to those of the adult. A prehallux or tibial sesamoid, serial homologue to the os falciforme or prepollex (a radial sesamoid), does not have an obvious functional role, and its presence might be the result of a common epigenetic control in the hand and the foot resulting in a non-adaptive structure in the latter.

Patterns of carpal development among anuran amphibians.

The unity and diversity of developmental processes in the vertebrate limb have singular importance in the interpretation of evolutionary hypotheses of tetrapod diversification. In anurans, the intraordinal diversity of forelimbs seems to be related to the fusion of distal carpals, whereas proximal carpals are invariable. However, there are different ontogenetic pathways involved in the differentiation of proximal carpals. This study presents a comparative analysis of early developmental features in one archeobatrachian and 23 neobatrachian species representing five families and explores the variability in the differentiation of carpal cartilages. We found new evidence supporting the presence of an embryonic intermedium that incorporates with the ulnare. Difference between the pipid Xenopus and the neobatrachians is interpreted as a change in the rate of differentiation of Distal Carpal 5 that does not affect the developmental pattern of digits. The developmental variability exhibited by the intermedium, radiale, and Element Y is combined in patterns that converge on the same adult carpal morphology among neobatrachians; these patterns appear to contain potentially useful phylogenetic information.

The effects of partial thyroidectomy on the development of the equine fetus.

A syndrome of congenital hypothyroidism and dysmaturity has been an important cause of reproductive loss and foal mortality in western Canada. The cause and pathogenesis of this syndrome is under investigation. One issue to be addressed is whether all the anomalies present in affected foals are produced concurrently by the same agent, or if affected foals are primarily hypothyroid in utero which induces the associated lesions. This study was designed to document the effects of fetal thyroidectomy, at about 215 days of gestation, on the growth and development of the equine fetus and to compare the anomalies present to those reported in the spontaneously occurring syndrome of foals in western Canada. Two sham-operated controls and 4 partially thyroidectomised foals were carried to term following surgery. Sham-operated control foals were normally developed. Partially thyroidectomised foals were hypothyroid; had hyperplastic thyroid gland remnants; abnormal behaviour and locomotor skills; and numerous, marked deficiencies in their skeletal development. The anomalies present in partially thyroidectomised foals were comparable to those reported in congenitally hypothyroid neonates of other species, including human infants, and were similar to those described in congenitally hypothyroid and dysmature foals reported in western Canada.