Emergence and evolution of Zfp36l3

Abstract

In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families. Zfp36l3 was not present in Dipodidae, or any families that branched earlier, indicating that this gene is exclusive to the Muroidea superfamily. We provide evidence that Zfp36l3 arose by retrotransposition of an mRNA encoded by a related gene, Zfp36l2 into an ancestral rodent X chromosome. Zfp36l3 has evolved rapidly since its origin, and numerous modifications have developed, including variations in start codon utilization, de novo intron formation by mechanisms including a nested retrotransposition, and the insertion of distinct repetitive regions. One of these repeat regions, a long alanine rich-sequence, is responsible for the full-time cytoplasmic localization of Mus musculus ZFP36L3. In contrast, this repeat sequence is lacking in Peromyscus maniculatus ZFP36L3, and this protein contains a novel nuclear export sequence that controls shuttling between the nucleus and cytosol. Zfp36l3 is an example of a recently acquired, rapidly evolving gene, and its various orthologues illustrate several different mechanisms by which new genes emerge and evolve.

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

“…Thus, there are currently 59 and 57 CCCH zinc finger proteins in mice and humans, respectively (TABLE 1). Zfp36l3 is a rodent-specific gene 6 and does not exist in humans. Human ZC3H21 is a pseudogene and not listed in TABLE 1.…”

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

“…to the placenta and yolk sac of certain rodents, but not other mammals Frederick et al, 2008;Gingerich et al, 2016). As we show here, its complete deficiency in the mouse leads to significant decreases in the numbers of surviving offspring.…”

“…Second, deep sequencing experiments have shown that its mRNA levels are the highest of the three family members found in human placenta (Saben et al, 2014). Finally, Zfp36l1 mRNA is the most highly expressed of the family members in the placentas from the rodent Nannospalax galili, a species very close evolutionarily to the rodents that express ZFP36L3, but which apparently does not express ZFP36L3 in the placenta (Gingerich et al, 2016). Although there are no good cellular models available of human syncytiotrophoblast cells, it might be possible to do specific mRNA knockdown experiments in either human trophoblast or choriocarcinoma cell lines that have been used to model placental transport systems in previous experiments (Ikeda et al, 2011;Lager et al, 2011).…”

“…A fourth mammalian gene in this family, Zfp36l3, is an X chromosomal gene expressed only in the yolk sac and placenta of certain rodents, including mice and rats Frederick et al, 2008;Gingerich et al, 2016). The ZFP36L3 protein differs from its other family members in several respects; for example, in contrast to the other family members, which are nucleocytoplasmic shuttling proteins (Phillips et al, 2002), the mouse and rat ZFP36L3 proteins contain long series of carboxylterminal repeats that serve to maintain the protein in the cytoplasm (Frederick et al, 2008).…”

An Ancient Family of RNA-Binding Proteins: Still Important!

“…It is thought to have arisen in an ancestor of these species about 25-30 million years ago through a process of retrotransposition involving Zfp36l2 [51]. It is an intronless, imprinted X-chromosome gene whose expression is limited to placenta and yolk sac in the mouse [52].…”