Platelet dense granules begin to selectively accumulate mepacrine during proplatelet formation

Hanby, Hayley A.; Bao, Jialing; Noh, Ji-Yoon; Jarocha, Danuta; Poncz, Mortimer; Weiss, Mitchell J.; Marks, Michael S.

doi:10.1182/bloodadvances.2017006726

Cited by 23 publications

(19 citation statements)

References 54 publications

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“…Because empty or immature granules may not be identified by TEM, mepacrine uptake was quantified as a measure of DG amount. 36,37 Mepacrine uptake was decreased by 45% in resting DKO platelets compared with WT ( Figure 4B). As a control, we observed that thrombin preactivated platelets incorporated minor amount of mepacrine, irrespective of their genotype ( Figure 4B).…”

Section: Rab32 and Rab38 Are Required For Dense Granule Formationmentioning

confidence: 98%

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

et al. 2019

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The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38. This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32, Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content.

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Section: Rab32 and Rab38 Are Required For Dense Granule Formationmentioning

confidence: 98%

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

et al. 2019

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“…Studies of these systems are likely to yield interesting surprises. For example, recent evidence suggests that dense granules do not mature until the final stages of platelet formation from megakaryocytes . Understanding the temporal regulation of this step will likely lead to new ideas regarding signaling pathways that can regulate LRO biogenesis in specific cell types.…”

Section: Perspectivesmentioning

confidence: 99%

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

Bowman

Bi‐Karchin

et al. 2019

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Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.

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“…Formation of platelet granules begins in megakaryocytes, but maturation continues in circulating platelets 12 , 13 . Human platelet granule deficiency syndromes, also referred to as storage pool disorders, and their related murine models have been a major source of study of platelet granulogenesis.…”

Section: Biogenesis Of Platelet Granulesmentioning

confidence: 99%

“…BLOC3 functions as a guanine nucleotide exchange factor for cell type-specific Rab GTPases, such as Rab32 and Rab38 in melanocytes 63 , 64 . A direct role of Rab32 and Rab38 in dense granule biogenesis in megakaryocytes has also been implicated 13 , 64 . RUNX1 mutations lead to dense granule but not α -granule deficiency due to dysregulation of Pallidin (HPS9) transcription 65 .…”

Section: Biogenesis Of Platelet Granulesmentioning

confidence: 99%

The life cycle of platelet granules

2018

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Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types—dense granules, α-granules, and lysosomes—although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways. Both are formed from the trans-Golgi network and early endosomes and mature in multivesicular bodies, but the formation of dense granules requires trafficking machinery different from that of α-granules. Following formation in the megakaryocyte body, both granule types are transported through and mature in long proplatelet extensions prior to the release of nascent platelets into the bloodstream. Granules remain stored in circulating platelets until platelet activation triggers the exocytosis of their contents. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, located on both the granules and target membranes, provide the mechanical energy that enables membrane fusion during both granulogenesis and exocytosis. The function of these core fusion engines is controlled by SNARE regulators, which direct the site, timing, and extent to which these SNAREs interact and consequently the resulting membrane fusion. In this review, we assess new developments in the study of platelet granules, from their generation to their exocytosis.

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Platelet dense granules begin to selectively accumulate mepacrine during proplatelet formation

Cited by 23 publications

References 54 publications

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

The life cycle of platelet granules

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