Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality

Abstract

Extracellular signal-regulated kinase 3 (Erk3) is an atypical member of the mitogen-activated protein (MAP) kinase family. No function has yet been ascribed to this MAP kinase. Here we show that targeted disruption of the Mapk6 gene (encoding Erk3) leads to intrauterine growth restriction, associated with marked pulmonary hypoplasia, and early neonatal death during the first day of life. Around 40% of Erk3 ؊/؊ neonates die within minutes after birth from acute respiratory failure. Erk3-deficient mice have normal lung-branching morphogenesis, but show delayed lung maturation characterized by decreased sacculation, atelectasis, and defective type II pneumocyte differentiation. Interestingly, in utero administration of glucocorticoid promoted fetal lung maturity and rescued differentiation of type II cells, but failed to alter the neonatal lethality. We observed that loss of Erk3 retards intrauterine growth, as reflected by a marked reduction in fetal lung, heart, and liver weights, and by low body weight at birth. Importantly, we found that insulin-like growth factor (IGF)-2 levels are decreased in the serum of Erk3-deficient mice. Our findings reveal a critical role for Erk3 in the establishment of fetal growth potential and pulmonary function in the mouse.AP kinases are a family of serine/threonine kinases that play a key role in transducing environmental stimuli into a wide range of intracellular responses (1). In mammals, 14 MAP kinase genes have been identified that define seven distinct MAP kinase signaling pathways (2). The classical MAP kinases are phosphorylated and activated by members of the MAP kinase kinase/Mek family and comprise the well-characterized Erk1/ Erk2, Jnk1/2/3, p38␣/␤/␥/␦, and Erk5 enzymes. Atypical MAP kinases include Erk3/Erk4, NLK, and Erk7. Much less is known about the mechanisms of regulation, substrate specificity, and physiological functions of this latter group of MAP kinases.The Erk3 gene was originally identified by homology-based cloning using the Erk1 cDNA as probe (3). Erk3 exists as a 100-kDa protein consisting of a kinase domain at the N terminus followed by a unique C-terminal extension of unknown function (3-5). Despite the significant homology of their kinase domains, several properties distinguish Erk3 from Erk1/Erk2 and other classical MAP kinases. Erk3 contains a single phospho-acceptor site in the activation loop instead of the canonical dual phosphorylation motif Thr-Xaa-Tyr. Unlike classical MAP kinases, activation loop phosphorylation of Erk3 is detected in resting cells and is minimally modulated by mitogenic or stress stimuli (6). Functionally, Erk3 does not phosphorylate generic MAP kinase substrates such as myelin basic protein [(7); unpublished data], indicating that it has different or more restricted substrate specificity. The only substrate of Erk3 that has been identified so far is the MAP kinase-activated protein kinase MK5 (8, 9). Structurally, Erk3 is most closely related to the MAP kinase Erk4. The two proteins display 73% amino acid identity in the ...

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