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 that