Differentiation of hairbulb pigment cell melanosomes in compound agouti and albino locus mouse mutants (Ay, a, c2J; C57BL/6J).

Our objective was to determine using electron microscopy how nonagouti (a), lethal yellow (Ay), and albino (c2J) genes affect the program of mouse hairbulb melanosome differentiation; 1,921 hairbulb melanosomes from four genotypes (a/a C/C = B,Ay/a C/C = Y, a/a c2J/c2J = BA, and Ay/a c2J/c2J = YA) were scored for developmental stage, length, and width. Qualitative and quantitative electron microscopy revealed the following. An albino locus-induced diminution of melanosome size suggests that the albino locus is involved in structural features of melanosomes not directly related to the synthesis and deployment of tyrosinase. Ratio data on melanosome length-to-width confirm that the agouti locus determines melanosome shape, either spherical or elliptical; melanization is not required for melanosomes to achieve their agouti-locus-determined shapes. YA (Ay/a c2J/c2J) melanosomes, characterized by poorly organized matrices, absence of active tyrosinase, unusually large membrane invaginations, and significantly smaller dimensions than those of BA (a/a c2J/c2J), showed additive effects of both Ay and c2J alleles. These data suggest that the albino locus plays a structural as well as functional (tyrosinase) role in the differentiation of mouse hairbulb melanosomes. The agouti locus, even in the absence of melanization, directs melanosome shape either via synthesis and deployment of agouti-locus-encoded matrix proteins or by other structural factors. The additive effects of Ay and c2J alleles in compound YA mutants document the importance of specific interactions both functional and structural between agouti and albino loci.

Progressive infertility in female lethal yellow mice (Ay/a; strain C57BL/6J).

Obese Ay/a females of 120 days or older, when compared to age-matched a/a controls (strain C57BL/6J), exhibited abnormal oestrous cyclicity characterized by reduced frequencies of true oestrous-stage smears, decreased mating success to proven a/a males, lowered uterine weights, and depressed ovulation rates. Exogenous gonadotrophins (PMSG/hCG) partly restored ovulation in obese Ay/a females to near control levels, demonstrating the sensitivity of Ay/a ovarian tissues to FSH and LH, at least at superovulatory levels. Concentrations of endogenous gonadotrophins and/or sensitivity of ovarian target cells to gonadotrophins may therefore be impaired in obese Ay/a females. Aberrant copulatory behaviour, reduced uterine weights, and depressed conception rates strongly suggest ovarian steroid deficiencies, perhaps secondary effects of reduced endogenous gonadotrophin activity. As in other obese rodent syndromes e.g. ob/ob, db/db, and fa/fa), a possible fundamental Ay-induced hypothalamic lesion is consistent with our data.