Ectopic dermal ridge configurations on the interdigital webbings and postaxial marginal portion of the hindlimb in Hammertoe mutant mice (Hm)

The effects of the hereditary malformation of Hammertoe mutant mice (gene symbol Hm) on the digital pads and dermal ridge configurations on their hindlimbs were examined. In the wild‐type (+/+) mice with normally separated digits, dermal ridges developed only on the pads. Heterozygous (Hm/+) and homozygous (Hm/Hm) mutant mice, however, had a broad big toe, fused interdigital soft tissues, reduced claws, an extra rudimentary postaxial digit and camptodactyly. The dermal ridges appeared not only on the pads, affected in their number and configurations, but also on the ventral surface of the interdigital webbings and postaxial marginal area exhibiting an extra rudimentary digit and webbing. These aberrant configurations may be related to the abnormal occurrence of programmed cell death (PCD) in the interdigital zones and the postaxial marginal portion in Hm/+ and Hm/Hm mice. That is, the diminished cell death may fail to decrease the cell density in the interdigital zones and postaxial marginal portion and result in the webbing and an extra rudimentary digit and webbing, respectively. Simultaneously, it could also interrupt the migration of surviving cells of these areas toward the neighboring digits and the distal area of the sole and produce the ectopic dermal ridges on the way to the as yet unformed (presumptive) digital and plantar volar pads. The present findings suggest that normal interdigital and pre/postaxial PCD contributes not only to the separation of digits, the initial formation of individual digits of different sizes, and the inhibition of the extra digit but also to the development of the presumptive digital and plantar pads, including dermal ridges. J. Morphol., 2008. © 2008 Wiley‐Liss, Inc.     

Sequential changes of programmed cell death in developing fetal mouse limbs and its possible roles in limb morphogenesis

Apoptotic cell death in the developing limb of mouse fetuses was examined sequentially on days 11–15 of gestation by means of Nile blue (NB) sulfate staining with special reference to its relation to limb morphogenesis. With some exceptions, programmed cell death (PCD) in the hand and foot was observed in the mesenchyme but not in the surface ectoderm. We found that during digital formation PCD begins at the proximal portion of the interdigital mesenchyme and subsequently expands distally. Therefore, the initial PCD that occurs in the interdigital zones may determine the proximal ends of digital separation and also contribute to the demarcation between the palm (sole) and digits (toes). During digital separation, the areas of PCD in the interdigital zones were found to become larger and expand distally on day 13, which may be necessary for the separation of digits and for determining the interdigital area to disappear. PCD in presumptive phalangeal joints was also found to proceed from proximal to more distal joints. The PCD in presumptive joints may be required for the separation of phalanges and metacarpal (metatarsal) bones and for the formation of joint cavities. In addition, intense PCD was observed in the radial (tibial) and ulnar (fibular) margins of the hand and foot plates for 4–5 days. Such PCD at marginal areas seems to prevent the formation of supernumerary digits (preaxial and postaxial polydactyly) and other digital malformations. Therefore, the timing when PCD commences and ends, the sites where PCD occurs, and the intensity, duration, and proximo-distal progress of PCD appear to be genetically determined, and the elimination of unnecessary cells by PCD may be essential for normal limb morphogenesis. The present findings also suggest that the normal progress of PCD in the hand and foot plates of rodent fetuses may prevent the formation of some limb malformations such as webbing fusion of digits, polydactyly, or cleft hand/foot. © 1996 Wiley-Liss, Inc.     

Dermal ridge development on the volar pads of the rat (Rattus norvegicus) and comparative study of pattern formation using inbred strains.

The development of dermal ridges, ridge configurations, and volar pad contours was investigated in the volar skin of the rat (Rattus norvegicus). The ridged structures corresponding to the epidermal ridges of primates exist only at the epidermal-dermal junction in the rat. Dermal specimens were prepared by treatment with alkaline solution and examined by toluidine blue staining and scanning electron microscopy, together with histological sections. Differentiation of dermal ridges began on day 18 of gestation on the palm followed by the sole. Ridges increased in number with advancing age. The process was complete approximately 2-3 days after birth, and sweat ducts began to develop simultaneously. As dermal ridges present various configurational patterns on palmar interdigital pad III, pattern formation on this pad was inspected in fetuses of three inbred strains possessing different pattern types, and in the hybrid progeny derived from them. Patterns and pad forms appeared to be under genetic control. It was revealed that the ridge arrangements, i.e., whorls, triradii, comb-like patterns, and others, are closely related to the pad contours during the developmental period, as hypothesized in primates.     

Palmar and plantar pads and flexion creases of genetic polydactyly mice (Pdn)

Attempts to gain a better understanding of the relationship between the epidermal ridge patterns (dermatoglyphics) and flexion creases on the volar aspects of human hands and feet and specific medical disorders led to a search for a suitable animal model, allowing studies of the fetal development of the pertinent structures. A common experimental animal, the rat (Rattus norvegicus), was found to be an excellent candidate, owing to the strong resemblance of the volar pads and flexion creases on its palmar and plantar surfaces to those of human subjects. A hereditary preaxial polydactyly mouse (Pdn) provides an opportunity to study the effects of this malformation on the surrounding morphological structures and, specifically, on the volar pads, i.e., the sites over which the dermatoglyphic patterns develop. The hands and feet of the wild‐type (+/+) mice show no anomalies, and their major pad and flexion crease configurations correspond to those of normal rats. The heterozygous (Pdn/+) mice, in spite of having a thumb/big toe with a duplicated distal phalanx on their hands/feet, did not display any alterations in palmar/plantar pads. The homozygous (Pdn/Pdn) mice have a protrusion in the thenar area and one to three supernumerary digits on the preaxial portion of both the hands and feet. The effect of these anomalies was found to be limited to the pad and flexion crease configurations in the preaxial areas; the postaxial sites were not affected. The original number of pads on the thenar/first interdigital areas of Pdn/Pdn mice was apparently identical to that of the +/+ and Pdn/+ mice. The preaxial protrusion, however, affected the number, size, and location of the pads observed in the newborn mice, resulting in varying pad configurations, such as fused and scattered pads or a pad cluster formed by gathering the neighboring pads. These pad modifications were induced by the preaxial plantar/palmar protrusion only and were not affected by the presence of supernumerary preaxial digits. In view of the similarities in the morphology and fetal development of human and mouse distal limbs, the present study is relevant to human subjects, particularly to the understanding of the significance of dermatoglyphic variations in individuals with specific medical disorders. Future studies of naturally occurring or experimentally induced limb malformations in mice or rats should provide valuable insights into the development of human hands and feet and into factors contributing to their congenital anomalies. J. Morphol. 239:87–96, 1999. © 1999 Wiley‐Liss, Inc.     

Palmar and plantar pads and flexion creases of the rat (Rattus norvegicus)

The recent detection of dermal ridge configurations on the volar pads of the rat (Rattus norvegicus) has created opportunities for experimental studies of dermatoglyphics. In the present work, the palmar and plantar surfaces of the rat were studied to establish the feasibility of comparative rat and human dermatoglyphic investigations. The studied features included the volar pads and flexion creases. The number and location of the palmar and plantar pads in the rat were found to be similar to those of humans. The exception was a previously unrecognized small pad on the palms and soles of the rat, located on the radial and tibial side, respectively, of the proximal component of the first interdigital pad. This pad has no parallel in human embryos. Rats were found to have flexion creases in the non-pad areas between the neighboring pads, similar in location and appearance to those of humans. Unlike humans, however, rats also have boundary creases, separating the pad and non-pad areas. The marked similarities in the morphology of the volar areas between rats and humans make the rat ideally suitable for experimental studies of dermatoglyphics and flexion creases. Results of such studies should be applicable to human developmental dermatoglyphics, including those pertaining to medical disorders. © 1994 Wiley-Liss, Inc.     

BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling

In vertebrate limbs that lack webbing, the embryonic interdigit region is removed by programmed cell death (PCD). Established models suggest that bone morphogenetic proteins (BMPs) directly trigger such PCD, although no direct genetic evidence exists for this. Alternatively, BMPs might indirectly affect PCD by regulating fibroblast growth factors (FGFs), which act as cell survival factors. Here, we inactivated the mouse BMP receptor gene Bmpr1a specifically in the limb bud apical ectodermal ridge (AER), a source of FGF activity. Early inactivation completely prevents AER formation. However, inactivation after limb bud initiation causes an upregulation of two AER-FGFs, Fgf4 and Fgf8, and a loss of interdigital PCD leading to webbed limbs. To determine whether excess FGF signaling inhibits interdigit PCD in these Bmpr1a mutant limbs, we performed double and triple AER-specific inactivations of Bmpr1a, Fgf4 and Fgf8. Webbing persists in AER-specific inactivations of Bmpr1a and Fgf8 owing to elevated Fgf4 expression. Inactivation of Bmpr1a, Fgf8 and one copy of Fgf4 eliminates webbing. We conclude that during normal embryogenesis, BMP signaling to the AER indirectly regulates interdigit PCD by regulating AER-FGFs, which act as survival factors for the interdigit mesenchyme.     

Development and variation of the anuran webbed feet (Amphibia, Anura)

Webbed feet evolved convergently in most groups of aquatic tetrapods. However, extensive webbing is not always limited to an aquatic life style. In Anurans, hind limbs display great variation, including absence, of interdigital membranes, which is explained by differential growth rates of digital and interdigital tissues during early limb development. In order to explore web diversification in anurans, this paper presents analyses of: (1) hind limb early development and its relationship to the expression of interdigital membranes; (2) intraordinal variation of interdigital membranes in adult feet; and (3) intraordinal variation of metatarsal and digit lengths, including comments on metatarsal development. Study of limb development is carried out in larval series of 12 anuran species. Analysis of intraordinal variation comprises a sample of adults of 111 species. We recognize two configurations in the autopodium bud: (1) paddle-like shape with digits differentiated within the confines of interdigital tissues, and (2) pointed autopodium with digits differentiated beyond interdigital tissues. These early differences are conserved in adult morphology, in which allometry and isometry of digit IV (and metatarsal IV) with respect to other digits (and metatarsals) result in asymmetrical and paddle-like autopodium, respectively. The paddle-like autopodium is restricted to fossil and extant pipids and the hylids Pseudis and Lysapsus , whereas the asymmetrical one is present in most anurans. Both configurations seem to represent an early divergence of the autopodium shape. The paddle-like configuration observed in hylids appears as a reversion to an ancient condition that results from a conserved program of limb development.  © 2008 The Linnean Society of London, Zoological Journal of the Linnean Society , 2008, 152 , 39–58.     

Anatomical features associated with preaxial duplication (pd): a recessive mutation in the rat

Preaxial polydactyly of the fore- and hindlimbs was found in Wistar-derived rats in 1978. Genetic analysis indicated that the polydactyly was due to the effects of an autosomal recessive gene (gene symbol; pd). Polydactylous homozygous rats had two or three pollices (six or seven digits) in the forelimbs and one to three preaxial extra digits (six to eight digits) in the hindlimbs. Skeletal examination revealed the presence of the extra carpal, metacarpal, and phalangeal bones that seemed to be complete or incomplete duplication of the navicular, greater multangular, first metacarpal, and phalanges of digit I in the forelimbs. In the hindlimbs, extra tarsal, metatarsal, and phalangeal bones were also observed preaxially. These extra elements seemed to be mirror-image duplications of the talus, navicular, second cuneiform, third cuneiform, cuboid, and metatarsals and phalanges of digits II-V with the absence of the first cuneiform, tibiale, first metatarsal, and phalanges of digit I. In addition, morphological changes were observed in the humerus, radius, and ulna in the forelimbs and femur, tibia, and fibula in the hindlimbs. Especially in the radius and tibia, thickening and bifurcation were found, indicating incomplete duplication of these bones. Based on these findings, the limb anomaly was classified as preaxial carpometacarpal/tarsometatarsal-type polydactyly with incomplete duplication of the radius and tibia. The mutant rats had other associated anomalies such as accessory spleens and cryptorchism. The males are sterile, whereas the females breed normally.     

人胎儿真皮乳头和皮纹发生的研究

本文用扫描电镜法研究了入胎儿的皮纹发生过程,包括初级真皮嵴、次级真皮嵴、真皮乳头和表皮隆线的发生。为研究人皮纹的发生和皮肤的异常提供了皮肤正常发育的形态学依据。共观察111例从第6周到第9个月胎儿的皮纹区皮肤,表明第3个月末胎儿开始形成初级真皮嵴,以后逐渐加深,至第16周嵴的顶端中央产生纵沟形成两条平行的次级真皮嵴;自19周后,次级真皮嵴局部隆起,由波浪形逐渐形成乳头。至30周乳头呈犬牙状。表皮隆线于第4—5月形成,随真皮乳头的增高而渐趋明显。至第6个月,全部皮纹图样已可辨认。本文还讨论了真皮乳头发生的过程。     

Fetal and postnatal development of palmar,plantar, and digital pads,and flexion creases of the rat (Rattus norvegicus)

Fetal development of the hands and feet of rats was investigated to determine the feasibility of using rats as an experimental model for studying the factors influencing early development of the hands and feet, and especially the dermatoglyphics in humans. Eighty rat fetuses of 14–21 days gestational age and 80 newborn rats of 0–7 days of age were used to study the morphological features of the palmar, plantar, and digital areas and to determine the timing of appearance and the location of the volar pads and flexion creases. Comparisons between analogous developmental stages of rat and human fetuses demonstrate striking similarities in overall fetal development. Marked differences, however, were found between rat and human fetuses in the timing of developmental milestones and in some morphological features. The results indicate that rats can serve as a useful experimental model in studies of the utility of the epidermal ridge configurations and flexion creases in medical disorders, provided that the differences in the timing of development are taken into consideration. © 1996 Wiley-Liss, Inc.     

A family study of dermatoglyphic traits in India: a search for major gene effects on palmar pattern ridge counts

Palmar pattern ridge counts were subjected to segregation analysis in an attempt to identify possible major gene effects on these dermatoglyphic traits. The phenotypes considered were total palmar pattern ridge count, and ridge counts for the right interdigital III and IV and left interdigital IV individual palmar areas (sample sizes were too small for the other palmar areas). Evidence of familial resemblance was found for all of the phenotypes studied, and initial evidence for a major effect was found for all but the right palm interdigital III ridge count. However, this initial evidence could be attributed to nongenetic effects in each case, including skewness in the trait distribution. Tests for agreement with Mendelian transmission frequencies were found to be very useful in discriminating between a non-Mendelian major effect and a major gene. We concluded against a major gene effect for any of these traits, and multifactorial inheritance remains a plausible alternative explanation for the familial resemblance.     

Experimental manipulation leading to induction of dorsal ectodermal ridges on normal limb buds results in a phenocopy of the eudiplopodia chick mutant

Elongation of chick limb buds depends on the presence of the apical ectodermal ridge which is induced by subjacent limb bud mesoderm. Recombination experiments have shown that the limb bud mesoderm loses the capacity to induce ridges by late stage 17. Moreover, in normal limb development only one ridge forms. However, in the eudiplopodia chick mutant accessory ectodermal ridges form on the dorsal surface of limb buds as late as stage 22. Tissue recombinant experiments show that the mutation affects the ectoderm, extending the time it responds to ridge induction (Fraser and Abbott, 1971a, Fraser and Abbott, 1971b while the mesoderm is normal. The result is polydactyly, with extra digits dorsal to the normal digits. Because eudiplopodia limb bud dorsal mesoderm can induce ridges at stage 22 but is unaffected by the gene, genetically normal dorsal limb bud mesoderm may also be able to induce ridges after stage 17. To test this possibility we grafted stages 14–18 flank ectoderm to normal limb bud dorsal mesoderm and found that mesoderm from stages 17 through 20 was able to induce a ridge and subsequently dorsal digits developed. Limbs with duplicate digits were similar to eudiplopodia limbs. In other experiments, stage 18, 19, and 20 leg bud dorsal ectoderm did not form ridges when grafted to leg bud dorsal mesoderm of the same stage, indicating a lack of response to the mesoderm. Finally, the inductive capacity of limb bud mesoderm appeared to be reduced compared to mesoderm at pre-limb bud stages. These experiments demonstrate a spatially generalized potential in limb bud dorsal mesoderm to induce ridges during the stages when the apical ridge is induced. The determination of where the ridge will form and the acquired inability of limb bud dorsal ectoderm to respond to induction by underlying mesoderm are necessary early pattern forming events which assure that a single proximodistal limb axis will form.     

Anatomical and microscopic study of the volar dermal ridges of the rat (Rattus norvegicus)

The epidermal ridges of the rat (Rattus norvegicus), which are distributed only on the volar pads and digital apices, were studied. Examination of the ridges was difficult on the epidermal surface, as the undulations expressed on the epidermis are weak. Therefore, the dermal surface, prepared by alkaline solution treatment, was inspected by scanning electron microscopy and staining with toluidine blue. The dermis of the pads and digital apices is composed of ridged and rippled areas. The ridged area, where sweat ducts are distributed, is constructed of grooves and ramparts. Frequently, the sweat duct is surrounded by a dermal collar, and the groove is separated by a dermal partition. The grooves and ramparts display dermatoglyphic configurations, such as whorls, loops, cusps, triradii, and some other patterns, which are peculiar to each pad and digital apex and comparable to dermatoglyphic patterns of man and other primates.     

Relationships of epidermal ridge patterns with body measurements and their possible evolutionary significance

It is commonly believed that in humans epidermal ridge patterns are in regression relative to nonhuman primates, and they play no role in adaptive processes. In contrast with this we have found relationships between anthropometric and dermatoglyphic measurements in a sample of 61 normal males. Anthropometric variables included limb, trunk, head, and face measures. Dermatoglyphic variables included finger ridge counts and pattern intensities and ridge breadth in the palmar interdigital area II. The strongest relationship is between the type and size of pattern on the thumb and the breadth of ridges, and wrist width, which accounts for nearly 30% of the total variance in these traits. These findings identify previously unknown sources of variation in dermatoglyphic patterns and indicate that the dermatoglyphic-anthropometric relationships might have resulted from selection pressures in evolution of modern man.     

Genetic basis of a-b, b-c and c-d ridge counts on human palms

The mechanism of inheritance of ridge count of palmar interdigital areas has been studied among Brahmans of Sagar town of Central India. The correlation coefficients between ridge counts in various family relationships lend support to the concept of an additive genetic model, especially for the b-c or second interdigital area.     

TGF-beta is required for programmed cell death in interdigital webs of the developing mouse limb

During limb formation massive cell death in the mesenchyme of the interdigital spaces accompanies the formation of free digits. Members of the transforming growth factor beta (TGF-) superfamily were discussed to play a key role in cell-cell interactions, important in the regulation of programmed cell death (PCD). TGF-beta itself is believed to be involved in epithelial-mesenchymal interactions. Here, we demonstrate that PCD is significantly reduced in interdigital spaces of the developing limbs of Tgfbeta2-/-Tgfbeta3-/- double knockouts. The regression of interdigital webs seems to be doses-dependent as interdigital mesenchyme is at least partly reduced in Tgfbeta2-/-Tgfbeta3+/- mutants, whereas interdigital zones of Tgfbeta2-/-Tgfbeta3-/- double knockouts reveal only minimal signs of regression. We conclude that TGF- is a critical extrinsic regulator of PCD.     

Prevention of polydactyly manifestation in Polydactyly Nagoya (Pdn) mice by administration of cytosine arabinoside during pregnancy

Male mice heterozygous for the dominant polydactyly gene Pdn (Polydactyly Nagoya) were crossed with normal or heterozygous females of the same strain. Pregnant females were treated with 5 mg/kg of cytosine arabinoside (Ara-C) on day 12 of gestation. The offspring were removed on day 18 of gestation and examined for external malformations, and the fore- and hindlimbs were examined by means of bone- and cartilage-stained cleared specimens. In +/+ x Pdn/+ matings, Pdn/+ fetuses, bearing preaxial polydactyly of the distal phalangeal type in the hindlimb and deformity of the 1st digit in the forelimb, were obtained in about 50% of the nontreated group. In treated fetuses, however, the incidence of polydactyly and deformity of the 1st digit decreased to 1.4 and 10.1%, respectively. Nontreated Pdn/Pdn fetuses exhibited preaxial polydactyly of the duplicated or triplicated metacarpal/metatarsal type both in the fore- and hindlimbs. In the treated Pdn/Pdn fetuses, the number of preaxial extra digits decreased in both limbs. Some hindlimbs of the treated Pdn/Pdn fetuses exhibited five metatarsals, normally. In the vitally stained specimens at 6 and 24 hours after injection of Ara-C, preaxial marginal necrotic zones (fMI) were observed in almost all of the treated embryos from +/+ x Pdn/+ matings. However, approximately half of the embryos did not exhibit fMI in the nontreated control group at the same stage. Those embryos deficient in fMI were regarded as Pdn/+. These findings indicated that a subteratogenic dose of Ara-C prevented the genetic expression of polydactyly in almost all Pdn/+ and some cases of Pdn/Pdn mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Furrows and dermal ridges of the hand in patients with alcohol embryopathy

Summary Palmar creases and dermal ridge patterns of 34 patients with alcohol embryopathy are compared with 470 healthy individuals. In alcohol embryopathy several typical deviations were noted. Palmar Creases. The interdigital part of the distal palmar crease is generally sharply bent, the proximal transverse crease is hypoplastic or missing, the thenar crease is commonly well marked. Simian creases and bridged palmar creases are more common in patients with alcohol embryopathy than in healthy individuals. Ridge Patterns of the Palm. The main line D coming from triradius d in patients with alcohol embryopathy mostly shows a low type of ending in the fourth interdigital area; in this area loops are twice as common as in healthy individuals. Patterns of the Fingertips. No deviations were noted in the distribution of whorls and loops, but virtually no arches were observed in patients with alcohol embryopathy. These anomalies suggest embryonic damage in the twelvth week of gestation.     

Finger and palmar dermatoglyphics in Seminole Indians of Florida

Hand prints of 146 Florida Seminoles were obtained at the Brighton, Big Cypress and Dania reservations and at the Indian Agency in Dania. Comparisons with other tribes of North American Indians (Comanche, Arapahoe, Navaho, Hopi and Pueblo) reveal similarities with respect to fingerprint indices, frequencies of patterns in all palmar areas, and transverseness of palmar ridges. Comparisons of Seminoles and other North American tribes with the Mayans of southern Mexico and Guatamala show striking differences in pattern frequencies in the thenar/first interdigital area of the palm. Among North American Indians, the frequency varies from 18.49% among Seminoles to 28.5% among Navahoes, whereas all Mayan tribes which have been studied range between 40 and 50%. Pattern frequencies are higher in the thenar/first interdigital area than in the hypothenar area among all Amerindians who have been tested. This trend is the reverse of that found in other racial groups. North, Central and South American Indians are similar with respect to relatively high finger pattern indices, low frequencies of patterns in the hypothenar area, low frequencies of accessory triradii in the interdigital areas and moderately transverse palmar ridges.     

Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death

Bone morphogenetic proteins (BMPs) are secreted signals that regulate apical ectodermal ridge (AER) functions and interdigital programmed cell death (PCD) of developing limb. However the identities of the intracellular mediators of these signals are unknown. To investigate the role of Smad proteins in BMP-regulated AER functions in limb development, we inactivated Smad1 and Smad5 selectively in AER and ventral ectoderm of developing limb, using Smad1 or/and Smad5 floxed alleles and an En1(Cre/+) knock-in allele. Single inactivation of either Smad1 or Smad5 did not result in limb abnormalities. However, the Smad1/Smad5 double mutants exhibited syndactyly due to a reduction in interdigital PCD and an increase in interdigital cell proliferation. Cell tracing experiments in the Smad1/Smad5 double mutants showed that ventral ectoderm became thicker and the descendents of ventral En1(Cre/+) expressing ectodermal cells were located at dorsal interdigital regions. At the molecular level, Fgf8 expression was prolonged in the interdigital ectoderm of embryonic day (E) 13 Smad1/Smad5 double mutants, suggesting that the ectopic Fgf8 expression may serve as a survival signal for interdigital epithelial and mesenchymal cells. Our result suggests that Smad1 and Smad5 are required and function redundantly as intracellular mediators for BMP signaling in the AER and ventral ectoderm. Smad1/Smad5 signaling in the AER and ventral ectoderm regulates interdigital tissue regression of developing limb. Our mutants with defects in interdigital PCD could also serve as a valuable model for investigation of PCD regulation machinery.