+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Retinoid-induced limb defects 1: Inhibition of cell proliferation in distal mesenchyme of limb buds in rats



Retinoid-induced limb defects 1: Inhibition of cell proliferation in distal mesenchyme of limb buds in rats



Reproductive Toxicology 13(2): 103-111



The present study was undertaken to investigate the effects of all-trans-retinoic acid (RA) on cell death and limb bud growth in forelimb buds and also to examine whether these events are involved in limb bone defects induced by RA in rats. RA was given at doses of 50 and 100 mg/kg to pregnant rats on Day 12 of pregnancy. Although RA did not show teratogenecity in the 50 mg/kg group, micromelia was observed in the 100 mg/kg group in all live fetuses on Day 21 of gestation. Micromelia was characterized by high incidences of proximodistal reduction of forearm bones without reduction of the humerus. The incidence of cell death in prechondrogenic areas, which differentiate into humerus and forearm bone, significantly increased 24 h after RA treatment in not only the 100 mg/kg, but also the 50 mg/kg, group. There was no difference in the incidence of cell death in the prechondrogenic area between the two groups. These observations indicate that the bone-specific defects were not the result of cell death alone in the prechondrogenic area. We examined the effects of RA on early forelimb bud growth, which is indispensable for the morphogenesis of the forelimb. Proximodistal length and protein content were decreased significantly in the forelimb bud 24 h after RA treatment at a dose of 100 mg/kg, but not 50 mg/kg. The immunohistochemical detection of bromodeoxyuridine (BrdU) incorporated into cells showed that at a dose of 100 mg/kg, cell proliferation was reduced in the distal mesenchyme, but not in the forearm-bone prechondrocytes of the forelimb bud. As the distal margin provides the cells differentiating into the prechondrocytes of future bones in the limb bud, these observations suggested that RA-induced inhibition of cell proliferation in the distal margin resulted in a decrease of forearm-bone prechondrocytes localized at more distal sites. We conclude that RA may inhibit the chondrogenesis of forearm bones by reducing cell proliferation in the distal margin of the forelimb bud, not by increasing cell death, and that this results in reduction defects in forearm bones.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 011297391

Download citation: RISBibTeXText

PMID: 10213517

DOI: 10.1016/s0890-6238(98)00069-0


Related references

Retinoid-induced limb defects 2: involvement of TGF-beta 2 in retinoid-induced inhibition of limb bud development. Reproductive Toxicology 13(2): 113-122, 1999

Thalidomide may inhibit proliferation of mesenchyme in human limb buds. Analytical Cellular Pathology 1(4): 247-254, 1989

Histological analysis of limb defects induced in developing limb buds of NMRI mouse embryos after oral administration of 3-3-dimethyl-1-phenyltriazene (DMPT) to their mother on day 10 of gestation. European Journal of Morphology 33(5): 491-508, 1995

Chondrogenesis in chick limb mesenchyme in vitro derived from distal limb bud tips: changes in cyclic AMP and in prostaglandin responsiveness. Journal of Cellular Physiology 136(1): 81-87, 1988

Neuronal guidance in dissected limb buds in cell culture and at ectopic locations in host limb buds. Society for Neuroscience Abstracts 11(1): 334, 1985

Formation of distal structures from stumps of chick wing buds at stages 24-25 following the grafting of quail tissue from X-irradiated distal limb buds. Journal of Experimental Zoology 267(4): 447-453, 1993

Relation of TGF-beta 2 to inhibition of limb bud chondrogenesis by retinoid in rats. Teratology 54(4): 191-197, 1996

Effect of cell association on in vitro chondrogenesis of mesenchyme cells from quail coturnix coturnix japonica limb buds. Cell Structure and Function 5(3): 239-246, 1980

Inhibition of myogenic cell migration by the application of antibodies raised against limb bud mesenchyme. Progress in Clinical and Biological Research 383b: 541-552, 1993

Mesenchyme with fgf-10 expression is responsible for regenerative capacity in Xenopus limb buds. Developmental Biology 219(1): 18-29, 2000

Differential effects of contralateral removal of regenerating limb buds on basal and proecdysial growth of remaining limb buds in the fiddler crab, Uca pugilator. American Zoologist 37(5): 116A, 1997

Vital staining for cell death in chick limb buds: a histochemical technique in the analysis of control of limb development. Acta Histochemica. Supplementband 32: 159-164, 1986

Patterns of dephosphorylating activities in the mesoderm of developing mouse limb buds 1. 5 nucleotidase nonspecific atp phospho hydrolase and alkaline phosphatase in normal fore limb buds. Archives de Biologie 94(3): 301-344, 1983

Development of the apical ectodermal ridge and changes in the subepidermal mesenchyme in mouse limb buds. Progress in Clinical and Biological Research 217b: 437-440, 1986

Development of apical ectodermal ridge and changes in subectodermal mesenchyme in mouse limb buds. Cell Differentiation 16(Suppl.): 165S, 1985