Mouse Phenotype

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Although embryonic development of the r/r mice appeared to be normal, as early as approximately 4 weeks of age they began to develop thick skin and patchy hair loss accounted for by dermal fibrosis. In older mice (> 5-6 months) skin abnormalities consisting of thickening and roughening, associated with patchy hair loss and small ulcerations were regularly observed.33 Indeed, in our initial report, we had not yet systematically examined the younger mice. Examination of skin sections revealed that the dermis from the r/r mutant mice was significantly thicker than that from control (r/r) mice and was filled with dense collagen fibers (Fig.10.4). The collagen fibers were irregular in form and penetrated deeply into the hypodermis. The overall increased thickness of the skin in the homozygous r/r mice, extending from the epidermis to the muscular layer, was accounted for by the increase in thickness in the dermis. The hair follicles appeared to be buried within the dense collagenous deposits whereas in control mice the hair follicles had their origin in the hypo-dermis. It is presumed that interference with the function of the hair follicles embedded in the dense collagenous matrix accounted for the hair loss. Several of these findings resemble those in the skin of patients with systemic sclerosis (scleroderma). Analysis of pepsin digests of mutant skin protein by SDS-PAGE and delayed reduction indicated that ~95% of the collagen was type I collagen with only traces of type III collagen.33 Interestingly, homozy-gous females and heterozygous male and female mice developed similar but milder skin abnormalities compared to those of homozygous males at the same age.

Another defect resulting from the mutant collagen became evident in the impaired reproductive ability of mutant females. In mammals, the uterine mass changes considerably during pregnancy and postpartum involution.40,41 In mice, the total uterine mass accounted for by collagen accumulation increases up to 20-fold during pregnancy, and after parturition the uterus rapidly recovers from prepregnant size.42 This postpartum involution is accomplished within the first two days after giving birth and involves transcriptional activation of the collagenase gene and increased release of collagenase extracellularly followed by the massive degradation of most of the collagen deposited in the uterus within a few days.40-42 In previously pregnant mutant r/r females, degradation of collagen was severely disturbed, leading to the accumulation of nodules in the uterine wall. These nodules consisted of large collagen aggregates, reflecting the impaired collagen degradation during the postpartum period (Fig. 10.5). The maintenance of a high collagen content in the postpartum uterus is presumably responsible for the reduced number of litters and decreased litter size of mutant females. Our results suggest that the massive degradation of collagen at the time of parturition is critically dependent on the presence of a functional cleavage site between Gly775 and Ile776 in the a1(I) chains of type I collagen. Our observations that there was a diffuse as well as nodular pattern to the collagen disposition in the r/r postpartum uterus suggests that the intensity of the normal resorptive process initiated at the time of parturition is not uniform throughout the uterus. So far we have only observed these changes in

Fig. 10.4. Histology of skin from collagenase-resistant (r/r) and wild-type (+/+) mice at ~6months of age. Paraffin-em-bedded sections were stained with hematoxylin and eosin (upper panels) and trichrome (lower panels). Photomicrographs were taken at same magnification. Note accumulation of collagen in the dermis from the r/r mice.

RESISTANT (r/r) AND MICE_

SKIN FROM COLLAGENASE-_WILD TYPE (+/+)

H&E

Trichrome r/r

Fig. 10.5. Histology of uteri from previous pregnant collagenase-resistant (r/r) and wild-type (+/+) mice. Sections were stained with hematoxylin and eosin with the exception of the sample from the r/r mouse labeled (B) which was stained with trichrome.

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