The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension (PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been clearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 +/- 14.5 versus 36.3 +/- 12.6 versus 24.2 +/- 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male-to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females [86%] versus 27 of 40 males [68%]). The disease has highly variable penetrance among families.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY The lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, while chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain- of function studies in the zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical co-alignment of lymphatic and blood vessels.

Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity.

The lymphatic vascular system is a hierarchically organized complex network essential for tissue fluid homeostasis, immune trafficking and absorption of dietary fats in the human body. Despite its importance, the assembly of the lymphatic network is still not fully understood. The zebrafish is a powerful model organism that enables study of lymphatic vessel development using high-resolution imaging and sophisticated genetic and experimental manipulation. Although several studies have described early lymphatic development in the fish, lymphatic development at later stages has not been completely elucidated. In this study, we generated a new Tg(mrc1a:egfp) y251 transgenic zebrafish that uses a mannose receptor, C type 1 (mrc1a) promoter to drive strong EGFP expression in lymphatic vessels at all stages of development and in adult zebrafish. We used this line to describe the assembly of the major vessels of the trunk lymphatic vascular network, including the later-developing collateral cardinal, spinal, superficial lateral and superficial intersegmental lymphatics. Our results show that major trunk lymphatic vessels are conserved in the zebrafish, and provide a thorough and complete description of trunk lymphatic vessel assembly.

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Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.

During embryonic development, cell type-specific transcription factors promote cell identities, while epigenetic modifications are thought to contribute to maintain these cell fates. Our understanding of how genetic and epigenetic modes of regulation work together to establish and maintain cellular identity is still limited, however. Here, we show that DNA methyltransferase 3bb.1 (dnmt3bb.1) is essential for maintenance of hematopoietic stem and progenitor cell (HSPC) fate as part of an early Notch-runx1-cmyb HSPC specification pathway in the zebrafish. Dnmt3bb.1 is expressed in HSPC downstream from Notch1 and runx1, and loss of Dnmt3bb.1 activity leads to reduced cmyb locus methylation, reduced cmyb expression, and gradual reduction in HSPCs. Ectopic overexpression of dnmt3bb.1 in non-hematopoietic cells is sufficient to methylate the cmyb locus, promote cmyb expression, and promote hematopoietic development. Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs.DOI: http://dx.doi.org/10.7554/eLife.11813.001

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