Characterization of Melanosomes in Murine Hermansky–Pudlak Syndrome: Mechanisms of Hypopigmentation
2004; Elsevier BV; Volume: 122; Issue: 2 Linguagem: Inglês
10.1046/j.0022-202x.2004.22117.x
ISSN1523-1747
Autores Tópico(s)Glaucoma and retinal disorders
ResumoThe Hermansky–Pudlak syndrome is a genetically heterogeneous autosomal recessive disorder affecting mice and humans, which causes oculocutaneous albinism, prolonged bleeding, and in some cases, pulmonary fibrosis or granulomatous colitis. We previously demonstrated that the gene defects causing murine Hermansky–Pudlak syndrome cause blocks in melanosome biogenesis and/or trafficking in 10 Hermansky–Pudlak syndrome strains. Here, we report an in vivo quantitative analysis on five additional murine models of the Hermansky–Pudlak syndrome. We demonstrate that all strains examined here except for ashen have defects in morphogenesis, the most severely affected is sandy, muted, and buff followed by subtle gray. The ashen strain only has a defect in secretion, as indicated by retention of melanosomes in melanocytes. We document three cellular mechanisms contributing to the hypopigmentation seen in the Hermansky–Pudlak syndrome: (1) exocytosis of immature hypopigmented melanosomes from melanocytes with subsequent keratinocyte uptake; (2) decreased intramelanocyte steady-state numbers of melanosomes available for transfer to keratinocytes; and (3) accumulation of melanosomes within melanocytes due to defective exocytosis, as seen in ashen. We also report that melanosomes in the DBA/2J strain, the parental strain of the Hermansky–Pudlak syndrome strain sandy, are abnormal, indicating that aberrant biogenesis of melanosomes may play a part in the pathogenesis of pigmentary glaucoma observed in these mice. The Hermansky–Pudlak syndrome is a genetically heterogeneous autosomal recessive disorder affecting mice and humans, which causes oculocutaneous albinism, prolonged bleeding, and in some cases, pulmonary fibrosis or granulomatous colitis. We previously demonstrated that the gene defects causing murine Hermansky–Pudlak syndrome cause blocks in melanosome biogenesis and/or trafficking in 10 Hermansky–Pudlak syndrome strains. Here, we report an in vivo quantitative analysis on five additional murine models of the Hermansky–Pudlak syndrome. We demonstrate that all strains examined here except for ashen have defects in morphogenesis, the most severely affected is sandy, muted, and buff followed by subtle gray. The ashen strain only has a defect in secretion, as indicated by retention of melanosomes in melanocytes. We document three cellular mechanisms contributing to the hypopigmentation seen in the Hermansky–Pudlak syndrome: (1) exocytosis of immature hypopigmented melanosomes from melanocytes with subsequent keratinocyte uptake; (2) decreased intramelanocyte steady-state numbers of melanosomes available for transfer to keratinocytes; and (3) accumulation of melanosomes within melanocytes due to defective exocytosis, as seen in ashen. We also report that melanosomes in the DBA/2J strain, the parental strain of the Hermansky–Pudlak syndrome strain sandy, are abnormal, indicating that aberrant biogenesis of melanosomes may play a part in the pathogenesis of pigmentary glaucoma observed in these mice. dopachrome tautomerase Hermansky–Pudlak Syndrome transmission electron microscopy tyrosinase-related protein 1 tyrosinase-related protein 2 The cellular regulation of organelle biogenesis is a tightly controlled process and dysregulation can cause significant disease. One disease of organelle biogenesis is the Hermansky–Pudlak syndrome (HPS), described in humans and mice (Swank et al., 1998Swank R.T. Novak E.K. McGarry M.P. Rusiniak M.E. Feng L. Mouse models of Hermansky–Pudlak Syndrome: A review.Pigment Cell Res. 1998; 11: 60-80Crossref PubMed Scopus (172) Google Scholar;Huizing et al., 2000Huizing M. Anikster Y. Gahl W.A. Hermansky–Pudlak syndrome and related disorders of organelle formation.Traffic. 2000; 1: 823-835Crossref PubMed Scopus (123) Google Scholar). In humans, six HPS genes have been identified, HPS1, AP3B1, HPS3, HPS4, HPS5, and HPS6 (Oh et al., 1996Oh J. Bailin T. Fukai K. et al.Positional cloning of a gene for Hermansky–Pudlak syndrome, a disorder of cytoplasmic organelles.Nat Genet. 1996; 14: 300-306Crossref PubMed Scopus (252) Google Scholar;Dell'Angelica et al., 1999Dell'Angelica E.C. Shotelersuk V. Aguilar R.C. Gahl W.A. Bonifacino J.S. Altered trafficking of lysosomal proteins in Hermansky–Pudlak Syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor.Mol Cell. 1999; 3: 11-21Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar;Anikster et al., 2001Anikster Y. Huizing M. White J. et al.Mutation of a new gene causes a unique form of Hermansky–Pudlak syndrome in a genetic isolate of central Puerto Rico.Nat Genet. 2001; 28: 376-380Crossref PubMed Scopus (170) Google Scholar;Suzuki et al., 2002Suzuki T. Li W. Zhang Q. et al.Hermansky–Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.Nat Genet. 2002; 30: 321-324Crossref PubMed Scopus (155) Google Scholar;Zhang et al., 2003Zhang Q. Zhao B. Li W. et al.Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky–Pudlak Syndrome types 5 and 6.Nat Genet. 2003; 33: 145-153Crossref PubMed Scopus (155) Google Scholar). In mice, at least 16 HPS genes have been noted, including six that are orthologous to the human genes (Gardner et al., 1997Gardner J.M. Wildenberg S.C. Keiper N.M. et al.The mouse pale ear (ep) mutation is the homologue of human Hermansky–Pudlak syndrome.Proc Natl Acad Sci USA. 1997; 94: 9238-9243Crossref PubMed Scopus (120) Google Scholar;Feng et al., 1999Feng L. Seymour A.B. Jiang S. et al.The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky–Pudlak syndrome and night blindness.Hum Mol Genet. 1999; 8: 323-330Crossref PubMed Scopus (211) Google Scholar;Suzuki et al., 2001Suzuki T. Li W. Zhang Q. et al.The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky–Pudlak Syndrome-3 gene.Genomics. 2001; 78: 30-37Crossref PubMed Scopus (68) Google Scholar,Suzuki et al., 2001Suzuki T. Li W. Zhang Q. et al.The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky–Pudlak Syndrome-3 gene.Genomics. 2001; 78: 30-37Crossref PubMed Scopus (68) Google Scholar). The genes in HPS for which putative functions have been ascribed appear to be defective in vesicle and organelle production and transport (Huizing et al., 2001Huizing M. Anikster Y. Gahl W.A. Hermansky–Pudlak syndrome and Chediak–Higashi syndrome: Disorders of vesicle formation and trafficking.Thromb Haemost. 2001; 86: 233-245PubMed Google Scholar;Marks and Seabra, 2001Marks M.S. Seabra M.C. The melanosome. Membrane dynamics in black and white.Nat Rev Mol Cell Biol. 2001; 2: 738-748Crossref PubMed Scopus (331) Google Scholar). The major pathologic conditions associated with HPS (cellular accumulation of ceroid-like pigment, oculocutaneous albinism, prolonged bleeding, and pulmonary fibrosis), implicate HPS genes in the biogenesis of lysosomes and lysosome-related cell-specific organelles such as melanosomes (found in pigment cells in skin, eye, ear, and meninges), platelet dense granules, and lung lamellar bodies (Marks and Seabra, 2001Marks M.S. Seabra M.C. The melanosome. Membrane dynamics in black and white.Nat Rev Mol Cell Biol. 2001; 2: 738-748Crossref PubMed Scopus (331) Google Scholar;Lyerla et al., 2003Lyerla T.A. Rusiniak M.E. Borchers M. et al.Aberrant lung structure, composition and function in a murine model of Hermansky–Pudlak syndrome.Am J Physiol Lung Cell Mol Physiol. 2003; 285: L643-L653Crossref PubMed Scopus (65) Google Scholar). Melanosomes, organelles in which the pigment melanin is packaged and secreted by skin melanocytes, provide an ideal model system for studying the defects in organelle biogenesis seen in HPS (Marks and Seabra, 2001Marks M.S. Seabra M.C. The melanosome. Membrane dynamics in black and white.Nat Rev Mol Cell Biol. 2001; 2: 738-748Crossref PubMed Scopus (331) Google Scholar). The normal morphology of melanosomes has been very well studied and described on an ultrastructural level. The maturation process of the melanosome proceeds through four morphologically distinct phases (Seiji et al., 1963Seiji M. Fitzpatrick T. Simpson R. Birbeck M. Chemical composition and terminology of specialized organelles (melanosomes and melanin granules) in mammalian melanocytes.Nature. 1963; 197: 1082-1084Crossref PubMed Scopus (119) Google Scholar): type I melanosomes share characteristics with late endosomes in having intralumenal vesicles; type II forms are elongated with intralumenal striations; type III forms have pigment deposited upon the striations; and type IV are completely filled with pigment. A number of melanocyte-specific proteins (tyrosinase, TYRP1, DCT/TRP2, gp100/Pmel, MART-1/melan-a, P protein) are targeted to the melanosome and their normal trafficking patterns have been studied to varying extents. Recent studies have shed light on early melanosome maturation steps, demonstrating that the gp100/Pmel protein resides in the limiting membrane of type I melanosomes, becomes internalized via incorporation into intralumenal vesicles and subsequently plays a role in the formation of the internal striations (Berson et al., 2001Berson J.F. Harper D.C. Tenza D. Raposo G. Marks M.S. Pmel17 initiates premelanosome morphogenesis within multivesicular bodies.Mol Biol Cell. 2001; 12: 3451-3464Crossref PubMed Scopus (248) Google Scholar,Berson et al., 2003Berson J.F. Theos A.C. Harper D.C. Tenza D. Raposo G. Marks M.S. Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis.J Cell Biol. 2003; 161: 521-533Crossref PubMed Scopus (214) Google Scholar;Raposo and Marks, 2002Raposo G. Marks M.S. The dark side of lysosome-related organelles: Specialization of the endocytic pathway for melanosome biogenesis.Traffic. 2002; 3: 237-248Crossref PubMed Scopus (120) Google Scholar). Subsequent to melanosome biogenesis and transport to the melanocyte periphery, the organelle or its contents are transferred to neighboring keratinocytes. Previously, we demonstrated that melanosomes in 10 HPS murine strains exhibit a range of biogenesis defects, resulting in morphologically abnormal organelles (Nguyen et al., 2002Nguyen T. Novak E.K. Kermani M. Fluhr J. Peters L.L. Swank R.T. Wei M.L. Melanosome morphologies in murine models of Hermansky–Pudlak Syndrome reflect blocks in organelle development.J Invest Dermatol. 2002; 119: 1156-1164Crossref PubMed Scopus (61) Google Scholar). We showed that each defective HPS gene introduced a block or rate-limiting step that resulted in the accumulation of immature melanosomal forms and were able to propose a map of where each gene affected the biogenesis pathway. Here we examine five additional HPS strains, and show that all but one strain have defects in melanosome biogenesis. We characterize the defects and propose that multiple mechanisms contribute to the hypopigmentation seen in HPS. All of the HPS strains studied here were initially identified on the basis of abnormal coat color and thus are by definition pigment diluted; however, only one strain, the buff strain, is on the black C57BL/6J genetic background. So whereas a direct comparison of the pigment in all of the mutant strains studied here was not feasible, the pigment dilution of each mutant strain relative to its parental strain could be compared Figure 1. The buff strain had a significant degree of pigment dilution, when compared with the control C57BL/6J strain. The ashen and subtle gray strains exhibit slight changes in pigmentation compared with the control C3H/HeSnJ strain. The sandy strain arose from DBA/2J. These two strains are interesting in that the control DBA/2J strain is homozygous for two mutations known to affect melanosome function: the MYO5α/dilute (Jenkins et al., 1981Jenkins N.A. Copeland N.G. Taylor B.A. Lee B.K. Dilute (d) coat colour mutation of DBA/2J mice is associated with the site of integration of an ecotropic MuLV genome.Nature. 1981; 293: 370-374Crossref PubMed Scopus (224) Google Scholar;Copeland et al., 1983Copeland N.G. Hutchison K.W. Jenkins N.A. Excision of the DBA ecotropic provirus in dilute coat-color revertants of mice occurs by homologous recombination involving the viral LTRs.Cell. 1983; 33: 379-387Abstract Full Text PDF PubMed Scopus (101) Google Scholar) and Tyrp1 (Moyer, 1963Moyer F.H. Genetic effects on melanosome fine structure and ontogeny in normal and malignant cells.Ann NY Acad Sci. 1963; 100: 584-606Crossref Scopus (65) Google Scholar;Rittenhouse, 1968Rittenhouse E. Genetic effect on fine structure and development of pigment granules in mouse hair bulb melanocytes. I. The b and d loci.Dev Biol. 1968; 17: 351-365Crossref PubMed Scopus (23) Google Scholar;Zdarsky et al., 1990Zdarsky E. Favor J. Jackson I.J. The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type.Genetics. 1990; 126: 443-449Crossref PubMed Google Scholar;Jackson et al., 1990Jackson I.J. Chambers D. Rinchik E.M. Bennett D.C. Characterization of TRP-1 mRNA levels in dominant and recessive mutations at the mouse brown (b) locus.Genetics. 1990; 126: 451-459Crossref PubMed Google Scholar;Corrigan, 2002Corrigan J. JAX NOTES.in: Jackson Laboratory, Bar Harbor, ME. Spring2002: 485Google Scholar) genes, each of which cause pigment dilution compared with the black C57BL/6 strain, which is wild type at these loci. The MYO5α/dilute gene product is the myosin Va motor protein (Mercer et al., 1991Mercer J.A. Seperack P.K. Strobel M.C. Copeland N.G. Jenkins N.A. Novel myosin heavy chain encoded by murine dilute coat colour locus.Nature. 1991; 349: 709-713Crossref PubMed Scopus (448) Google Scholar) and mutations in the dilute gene cause retention of melanosomes in the cell body (Rittenhouse, 1968Rittenhouse E. Genetic effect on fine structure and development of pigment granules in mouse hair bulb melanocytes. I. The b and d loci.Dev Biol. 1968; 17: 351-365Crossref PubMed Scopus (23) Google Scholar;Provance et al., 1996Provance Jr, D.W. Wei M. Ipe V. Mercer J.A. Cultured melanocytes from dilute mutant mice exhibit dendritic morphology and altered melanosome distribution.Proc Natl Acad Sci USA. 1996; 93: 14554-14558Crossref PubMed Scopus (145) Google Scholar;Wu et al., 1998Wu X. Bowers B. Rao K. Wei Q. Hammer J.A.R. Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function In vivo.J Cell Biol. 1998; 143: 1899-1918Crossref PubMed Scopus (328) Google Scholar). The TYRP1 protein is restricted in expression to pigment cells, is targeted to the melanosome limiting membrane and is an enzyme functioning in pigment synthesis (Sarangarajan and Boissy, 2001Sarangarajan R. Boissy R.E. Tyrp1 and oculocutaneous albinism type 3.Pigment Cell Res. 2001; 14: 437-444Crossref PubMed Scopus (78) Google Scholar). It can be seen that in the sandy strain, however, the additional HPS gene mutation is a cause of further marked pigment loss. The muted strain exhibits a small but significant measurable pigmentation difference from its heterozygote littermate control. To determine if the HPS gene mutations in the strains studied here caused defective morphogenesis, melanosome morphology in skin tissue was examined by transmission electron microscopy. Three of the control strains (C57BL/6, C3H/HeSnJ, mu/+) had numerous, completely pigmented, ellipsoidal type IV melanosomes Figure 2. The fourth control strain, DBA/2J, had abnormal melanosomal morphology. Whereas there were many fully pigmented melanosomes in DBA/2J, these were slightly irregularly shaped, surrounded by "wavy" or "ruffled" limiting membranes that also contained peripheral granular material. No normally striated melanosomal type II or III forms were observed in DBA2/J. Rather, intermediate forms that had intralumenal short, truncated curvilinear segments, suggesting incomplete or abnormal striations, were seen. Melanosomes in the initial stages of pigmentation had pigment accumulated like "beads on a string" along these abnormal linear segments. Several melanosomes in this strain appeared to be two mature melanosomes that had undergone fusion in that they shared a common limiting membrane but had two separate elliptical fully pigmented cores Figure 2c. Two of the mutant strains, ashen and subtle gray, also had numerous mature melanosomal forms, similar to those seen in the control C57BL/6 and C3H/HeSnJ strains, and these two strains seemed to have fairly normal melanosomal morphology overall Figure 2b. In contrast, the buff, sandy, and muted strains had a marked absence of fully pigmented elongated forms. The sandy strain had the most morphologically abnormal appearing melanosomes Figure 2c. Few abnormally striated forms were observed, and very few fully pigmented structures or recognizable type I structures were observed. Instead, there were numerous abnormal vesicular forms with internal amorphous grainy material, with shapes that were unevenly spherical or very irregular; some of these abnormal vesicular forms contained foci of pigment. The muted strain was similar to sandy in having an accumulation of abnormal vesicular forms, but also had many striated melanosomal forms Figure 2c. Both the buff and muted strains had fully pigmented round forms but buff melanosomes appeared smaller than those observed in its control strain Figure 2a. Because of the observation that buff appeared to have lost the regulation of melanosome size, the average size of mature melanosomes in the cell body of melanocytes was measured to quantify any differences with control strains. The buff melanosomes had a significantly diminished size Figure 3. The other mutant strains did not show a significant difference in fully pigmented melanosome size when compared with their respective control strains (data not shown). One marker of melanosomal maturation is a size increase as melanosomes progress from type I to type IV, as occurs in the C57BL/6 strain (Nguyen et al., 2002Nguyen T. Novak E.K. Kermani M. Fluhr J. Peters L.L. Swank R.T. Wei M.L. Melanosome morphologies in murine models of Hermansky–Pudlak Syndrome reflect blocks in organelle development.J Invest Dermatol. 2002; 119: 1156-1164Crossref PubMed Scopus (61) Google Scholar). Size progression is also evident in the C3H/HeSnJ control strain, but less so in the DBA/2J control strain Figure 4, in which abnormal melanosomal morphology was noted above. In order to assess the extent of melanosomal maturation in each of the mutant strains, the sizes of the different melanosomal forms were measured and compared. The size progression is preserved in the buff, ashen, and subtle gray strains, but is absent in the sandy and muted strains, which suggests an impaired maturation process in these two strains. Examination of the intramelanocyte steady-state distribution of the different melanosomal types can detect if a block in morphogenesis has occurred or if a rate-limiting step is introduced into the biogenetic pathway, because immature precursors will accumulate and mature forms will either be absent or relatively decreased in number. So, to assess at what step melanosomal biogenesis was impaired in each of these strains, the percentage of types I, II/III, and IV forms were determined for each strain Figure 5. Three strains (buff, sandy, and muted) had evidence of significant blocks in melanosome biogenesis. These three strains showed a decrease in the percentage of mature melanosomes present and a concomitant increase in the proportion of abnormal vesicular forms that could not be identified as a normal melanosomal stage. These abnormal vesicular forms were also present as a minor proportion of organelles in the C57BL/6, C3H/HeSnJ and muted heterozygote control strains, and to a greater extent in the DBA/2J control strain. The abnormal vesicular forms are detailed in Table II and Figure 6. Another strain, subtle gray, is aptly named in that the effect on melanosome biogenesis is mild, and a relatively small accumulation of immature type I and II/III forms is seen in comparison with the control CH3/HeSnJ strain with a concomitant small decrease in the proportion of fully pigmented forms. Melanosomes in the ashen strain are predominantly mature, with an increase in the proportion of mature forms compared with in the control strain, indicating the absence of any impairment of biogenesis in this strain.Table IIFeatures of abnormal vesicular structures accumulated in melanocytesDBA/2JSandyMutedBuffdark gray grainy lumenaSee Figure 6.dark gray grainy lumendark gray grainy lumendark gray grainy lumenmultiple pigmented coresbSee Figure 6.multiple pigmented coresdark gray lumen with black coremultiple pigmented coresdark gray lumen, ILV*ILV: intralumental vesiclesdark gray lumen, ILVdark gray lumen, ILVcSee Figure 6.partial pigment, no ILV or striationsdSee Figure 6.dark gray lumen with black coreeSee Figure 6.dark gray lumen with multiple gray cores fSee Figure 6.* ILV: intralumental vesiclesa–f See Figure 6. Open table in a new tab Figure 6View Large Image Figure ViewerDownload (PPT) Previous studies of cultured ashen melanocytes showed that as a result of the mutation in the Rab27a gene, melanosomes are not transported to the dendrites but remain in a perinuclear distribution, and are not efficiently exocytosed (Provance et al., 1996Provance Jr, D.W. Wei M. Ipe V. Mercer J.A. Cultured melanocytes from dilute mutant mice exhibit dendritic morphology and altered melanosome distribution.Proc Natl Acad Sci USA. 1996; 93: 14554-14558Crossref PubMed Scopus (145) Google Scholar;Wu et al., 1998Wu X. Bowers B. Rao K. Wei Q. Hammer J.A.R. Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function In vivo.J Cell Biol. 1998; 143: 1899-1918Crossref PubMed Scopus (328) Google Scholar). To confirm that this is true in vivo as well, the number of melanosomes per unit area of melanocyte cytoplasm was determined Figure 7. The number of ashen melanosomes per unit area was increased by 72% compared with in the control strain, consistent with melanosomes being retained within the cell body. In contrast, in the subtle gray and muted strains, the number of melanosomes per unit area was decreased compared with in control strains, suggesting that either the rate of biogenesis was slowed or that there was an ongoing destruction of abnormal organelles. Another alternative, that an increased rate of exocytosis of the melanosomes was occurring, was unlikely, as an increase in the number of melanosomes in the neighboring keratinocytes was not observed (data not shown). We previously observed that pigmentation in HPS strains varied inversely with the percentage of hypopigmented melanosomal forms present in melanocytes and suggested that hypopigmentation may result from the exocytosis of an increased proportion of unpigmented or hypopigmented melanosomal forms (Nguyen et al., 2002Nguyen T. Novak E.K. Kermani M. Fluhr J. Peters L.L. Swank R.T. Wei M.L. Melanosome morphologies in murine models of Hermansky–Pudlak Syndrome reflect blocks in organelle development.J Invest Dermatol. 2002; 119: 1156-1164Crossref PubMed Scopus (61) Google Scholar). In this study, we observed evidence of immature melanosomal forms in the process of exocytosis from melanocytes Figure 8a. The ability of these exocytosed immature melanosomal forms to be internalized by neighboring keratinocytes was indicated by the appearance of these forms in the cytoplasm of keratinocytes. In the muted and buff strains, type II and III melanosomes were observed in keratinocytes surrounding melanocytes Figure 8b and/or in the hair shaft (data not shown). Similar findings were observed in the pallid, cappuccino, and reduced pigmentation HPS strains. In the control C57BL/6 and C3H/HeSnJ control strains, only type IV forms comprised the many melanosomes observed in keratinocytes surrounding melanocytes (data not shown). Similarly, in the mu/+ control keratinocytes, the majority of melanosomes were type IV, with very few type III forms observed. Notably, in the subtle gray and ashen mutants, only fully pigmented melanosomes were observed in keratinocytes. Interestingly, melanosomes in ashen keratinocytes were present singly, whereas in the other mutant strains, melanosomes in keratinocytes were grouped in membrane limited structures, likely phagolysosomes. Very few melanosomes were seen in keratinocytes surrounding DBA/2J melanocytes, due to the mutant MYO5α/dilute gene, which causes retention of melanosomes in melanocytes (Rittenhouse, 1968Rittenhouse E. Genetic effect on fine structure and development of pigment granules in mouse hair bulb melanocytes. I. The b and d loci.Dev Biol. 1968; 17: 351-365Crossref PubMed Scopus (23) Google Scholar;Provance et al., 1996Provance Jr, D.W. Wei M. Ipe V. Mercer J.A. Cultured melanocytes from dilute mutant mice exhibit dendritic morphology and altered melanosome distribution.Proc Natl Acad Sci USA. 1996; 93: 14554-14558Crossref PubMed Scopus (145) Google Scholar;Wu et al., 1998Wu X. Bowers B. Rao K. Wei Q. Hammer J.A.R. Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function In vivo.J Cell Biol. 1998; 143: 1899-1918Crossref PubMed Scopus (328) Google Scholar). In sandy, the mutant strain derived from DBA/2J, melanosomes of the same abnormal morphology as seen in melanocytes (not identifiable as types I–IV) were seen in keratinocytes indicating that the ability to be secreted was not completely abolished despite the abnormal morphology. This in vivo quantitative study demonstrates that the murine HPS strains, muted, sandy, buff, and subtle gray all have defects in melanosomal maturation, whereas the ashen strain has no evidence of defective biogenesis, but is characterized by retention of melanosomes within the melanocyte cell body. This study also documents the exocytosis of immature melanosome forms and uptake of those forms by keratinocytes. A striking feature of HPS gene products is that many of them form protein complexes with one another. These complexes have been termed BLOC-1 (pallid, cappuccino, muted proteins, and possibly reduced pigmentation protein), BLOC-2 (ruby eye and ruby eye-2 proteins), and BLOC-3 and BLOC-4 (HPS1/pale ear and HPS4/light ear proteins) (Falcon-Perez et al., 2002Falcon-Perez J.M. Starcevic M. Gautam R. Dell'Angelica E.C. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules.J Biol Chem. 2002; 277: 28191-28199Crossref PubMed Scopus (136) Google Scholar;Moriyama and Bonifacino, 2002Moriyama K. Bonifacino J.S. Pallidin is a component of a multi-protein complex involved in the biogenesis of lysosome-related organelles.Traffic. 2002; 3: 666-677Crossref PubMed Scopus (57) Google Scholar;Chiang et al., 2003Chiang P.W. Oiso N. Gautam R. Swank R.T. Spritz R.A. The Hermansky–Pudlak syndrome 1 (HPS1) and HPS4 proteins are components of two complexes, BLOC-3 and BLOC-4, involved in the biogenesis of lysosome-related organelles.J Biol Chem. 2003https://doi.org/10.1074/jbc.M300090200]Crossref Scopus (82) Google Scholar;Ciciotte et al., 2003Ciciotte S.L. Gwynn B. Moriyama K. Huizing M. Gahl W.A. Bonifacino J.S. Peters L.L. Cappuccino, a mouse model of Hermansky–Pudlak Syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1).Blood. 2003https://doi.org/10.1182/blood-2003-01-0020Crossref Scopus (69) Google Scholar;Martina et al., 2003Martina J.A. Moriyama K. Bonifacino J.S. BLOC-3, a protein complex containing the Hermansky–Pudlak syndrome gene products HPS1 and HPS4.J Biol Chem. 2003; 278: 29376-29384Crossref PubMed Scopus (99) Google Scholar;Zhang et al., 2003Zhang Q. Zhao B. Li W. et al.Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky–Pudlak Syndrome types 5 and 6.Nat Genet. 2003; 33: 145-153Crossref PubMed Scopus (155) Google Scholar). Our results here together with our previously reported results (Nguyen et al., 2002Nguyen T. Novak E.K. Kermani M. Fluhr J. Peters L.L. Swank R.T. Wei M.L. Melanosome morphologies in murine models of Hermansky–Pudlak Syndrome reflect blocks in organelle development.J Invest Dermatol. 2002; 119: 1156-1164Crossref PubMed Scopus (61) Google Scholar) reveal that: (1) the melanosome morphology of the BLOC-3/4 mutants pale ear and light ear are indistinguishable qualitatively and quantitatively; (2) the BLOC-1 mutants pallid and cappuccino also have very similar morphologies, both qualitatively and quantitatively; (3) the morphology of the BLOC-2 mutants ruby eye and ruby eye-2 are similar except that the melanosome size is larger on average in ruby eye. The BLOC-1 mutant muted can be distinguished from the BLOC-1 pallid and cappuccino mutants by the presence of an increased proportion of pigmented melanosomal forms, but the phenotype in muted is very similar to that of the reduced pigmentation mutant, predicted to be a possible component of BLOC-1 (Falcon-Perez et al., 2002Falcon-Perez J.M. Starcevic M. Gautam R. Dell'Angelica E.C. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules.J Biol Chem. 2002; 277: 28191-28199Crossref PubMed Scopus (136) Google Scholar;Moriyama and Bonifacino, 2002Moriyama K. Bonifacino J.S. Pallidin is a component of a multi-protein complex involved in the biogenesis of lysosome-related organelles.Traffic. 2002; 3: 666-677Crossref PubMed Scopus (57) Google Scholar). Thus the melanosome morphologies in HPS mutants appear to r
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