The zebrafish progranulin gene family and antisense transcripts

BACKGROUND: Progranulin is an epithelial tissue growth factor (also known as proepithelin, acrogranin and PC-cell-derived growth factor) that has been implicated in development, wound healing and in the progression of many cancers. The single mammalian progranulin gene encodes a glycoprotein precursor consisting of seven and one half tandemly repeated non-identical copies of the cystine-rich granulin motif. A genome-wide duplication event hypothesized to have occurred at the base of the teleost radiation predicts that mammalian progranulin may be represented by two co-orthologues in zebrafish. RESULTS: The cDNAs encoding two zebrafish granulin precursors, progranulins-A and -B, were characterized and found to contain 10 and 9 copies of the granulin motif respectively. The cDNAs and genes encoding the two forms of granulin, progranulins-1 and -2, were also cloned and sequenced. Both latter peptides were found to be encoded by precursors with a simplified architecture consisting of one and one half copies of the granulin motif. A cDNA encoding a chimeric progranulin which likely arises through the mechanism of trans-splicing between grn1 and grn2 was also characterized. A non-coding RNA gene with antisense complementarity to both grn1 and grn2 was identified which may have functional implications with respect to gene dosage, as well as in restricting the formation of the chimeric form of progranulin. Chromosomal localization of the four progranulin (grn) genes reveals syntenic conservation for grna only, suggesting that it is the true orthologue of mammalian grn. RT-PCR and whole-mount in situ hybridization analysis of zebrafish grns during development reveals that combined expression of grna and grnb, but not grn1 and grn2, recapitulate many of the expression patterns observed for the murine counterpart. This includes maternal deposition, widespread central nervous system distribution and specific localization within the epithelial compartments of various organs. CONCLUSION: In support of the duplication-degeneration-complementation model of duplicate gene retention, partitioning of expression between grna and grnb was observed in the intermediate cell mass and yolk syncytial layer, respectively. Taken together these expression patterns suggest that the function of an ancestral grn gene has been devolved upon four paralogues in zebrafish

Aging all over the place : a multidisciplinary framework, that considers place and life trajectories of older adults within their communities

Abstract : Purpose This conceptual paper describes Aging All Over the Place (AAOP), a federative framework for action, research and policy that considers older adults’ diverse experiences of place and life trajectories, along with person-centered care. Design/methodology/approach The framework was developed through group discussions, followed by an appraisal of aging models and validation during workshops with experts, including older adults. Findings Every residential setting and location where older adults go should be considered a ‘place’, flexible and adaptable enough so that aging in place becomes aging all over the place. Healthcare professionals, policymakers and researchers are encouraged to collaborate around four axes: 1) biopsychosocial health and empowerment; 2) welcoming, caring, mobilized, and supportive community; 3) spatiotemporal life and care trajectories; and 4) out-of-home care and services. When consulted, a Seniors Committee showed appreciation for flexible person-centered care, recognition of life transitions and care trajectories, and meaningfulness of the name. Originality Building on the introduction of an ecological experience of aging, AAOP broadens the concept of care as well as the political and research agenda by greater integration of community and clinical actions. AAOP also endeavors to avoid patronizing older adults and engage society in strengthening circles of benevolence surrounding older adults, regardless of their residential setting. AAOP’s applicability is evidenced by existing projects that shared its approach. Social implications Population aging and the pandemic call for intersectoral actions and for stakeholders beyond healthcare to act as community leaders. AAOP proposes opportunities to connect environmental determinants of health and person-centered care

The zebrafish progranulin gene family /

Granulins are small cysteine-rich peptide growth factors that, in mammals, are derived from a common glycoprotein precursor (progranulin) containing one half and seven non-identical tandemly repeated granulin domains. While there is evidence for only one progranulin gene in mammalian genomes, work presented in this thesis demonstrates that granulins form an extended gene family in teleost fish. Two zebrafish genes that constitute likely co-orthologues to mammalian progranulin, progranulin-a and progranulin-b, encode precursors that encode 10 and 9 copies of the granulin motif, respectively. Two additional genes in zebrafish, designated progranulin-1 and progranulin-2, each give rise to precursors consisting of one and one-half granulin-like repeats only. The progranulin-1 and progranulin-2 genes are organized in tandem, and possess exonic complementarity to a single non-coding RNA gene transcribed in the antisense orientation from the complementary DNA strand. A cDNA encoding a chimeric precursor consisting of the amino-terminal progranulin-1 followed by the carboxyl-terminal region of progranulin-2 was characterized and is likely generated through the mechanism of splicing in trans between the two primary transcripts for progranulin-1 and progranulin-2. Chromosomal assignment of the zebrafish progranulin genes indicates that progranulin-a, but not progranulin-b, is located on a chromosome that displays syntenic correspondence to mammalian progranulin. Cumulatively, the data suggest that an ancestral progranulin gene was duplicated at the base of the vertebrate radiation to generate precursors with distinct architectures and that one was lost in the lineage leading to tetrapods after the split between sarcopterygians and actinopterygians. Like their mammalian counterpart, the expression of the zebrafish progranulins is widespread in adult tissues. During development, the maternal expression of progranulin-a and progranulin-b parallels tha