Brain-Specific Deletion of Extracellular Signal-Regulated Kinase 2 Mitogen-Activated Protein Kinase Leads to Aberrant Cortical Collagen Deposition

Abstract

The mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2 are essential intracellular mediators of numerous transmembrane signals. To investigate neural-specific functions of ERK2 in the brain, we used a Cre/lox strategy using Nestin:Cre to drive recombination in neural precursor cells. Nestin:Cre;ERK2 fl/fl conditional knockout (cKO) mice have architecturally normal brains and no gross behavioral deficits. However, all cKO mice developed early-onset (postnatal day 35 to 40) frontal cortical astrogliosis, without evidence of neuronal degeneration. Frontoparietal cortical gray matter, but not underlying white matter, was found to contain abundant pericapillary and parenchymal reticulin fibrils, which were shown by immunohistochemistry to contain fibrillar collagens, including type I collagen. ERK1 general KO mice showed neither fibrils nor astrogliosis, indicating a specific role for ERK2 in the regulation of brain collagen. Collagen fibrils were also observed to a lesser extent in GFAP:Cre;ERK2 The extracellular signal-regulated kinase (ERK) family of mitogen-activated protein kinases (MAPKs) has been intensely studied for roles in brain development, including control of both axonal 1,2 and dendritic 3 growth. Astroglial process extension is also dependent on ERK signaling. 4 Recent work strongly implicates ERK-mediated signaling in synaptic plasticity and memory formation, and mutations in ERK2 and other ERK pathway components are known to underlie some forms of inherited human cognitive disorders.5-7 ERK MAPK activation is also linked to astroglial activation in several forms of central nervous system (CNS) injury. 8 -10 To directly test the importance of ERK MAPKs in vivo, gene knockout approaches are needed. Whereas ERK1 general knockout (KO) mice are viable and have architecturally normal brains, 11 general KO of ERK2 is embryonic lethal, because of defects in mesoderm differentiation and placental development.12-14 Thus, conditional KO (cKO) strategies are necessary to study brain-specific roles of ERK2. Two recent reports 15,16 describe aspects of the developmental phenotype resulting from CNS-specific KO of the mapk1 gene, encoding ERK2. We now present a novel aspect of the adult phenotype of a brain-specific ERK2 cKO driven by Nestin:Cre. Our findings suggest an unexpected and specific role for this classical MAPK member in the regulation of brain collagen deposition. Materials and Methods Transgenic Mice and PCR GenotypingThe generation of strain harboring a conditional ("floxed") mapk1 mutant allele (Mapk1 flox/flox ; subsequently referredSupported by grants NS047378 (to J.W.M.) and NS032779, MH57014, NS13546, and NS057098 (to G.E.L.).

ERK2 Contributes to the Control of Social Behaviors in Mice

“…4), indicating that ERK2 may be required for regulation of astrogliosis. This is consistent with previous reports, which demonstrated that inhibition of the MEK-ERK pathway resulted in enhanced generation of astrocytes (Paquin et al, 2005;Samuels et al, 2008;Heffron et al, 2009). GFAP ϩ cells seem to be more abundant in outer layers than inner layers of cortices (Fig.…”

“…ERK is activated in social behavior circuits during resident-intruder aggression tests (Trainor et al, 2010). On the other hand, it was reported that mice with the deletion of ERK2 in the CNS (Heffron et al, 2009) did not exhibit prominent anomalies in behavior tests, although they did not perform social behavior tests. They used breeding pairs consisted of male nestin-creϩ; Erk2 flox/ϩ mated with female nestin-creϪ; Erk2 flox/flox mice: all mice in their study were borne and reared by control mothers.…”

Neurodevelopmental effects of insulin-like growth factor signaling

“…the other known Erk), in cultured Erk2-null stem cells does not affect this outcome, the normal proliferation in Erk2 null mutants is unlikely due to Erk1 compensation. Studies of mice with an Erk deletion specifically in neural precursors have proven inconclusive (Heffron et al, 2009; Samuels et al, 2008; Satoh et al, 2007; Satoh et al, 2011). These data suggest that Erk is not essential in cell proliferation mediated by IGF signaling and/or other growth signaling.…”

Zinc and the ERK Kinases in the Developing Brain

“…The role of ERK2 in neural development was studied by conditional deletion of ERK2 in neural precursor cells using the nestin promoter to drive Cre recombinase expression. Surprisingly, these mice developed grossly normal brain structures, and no behavioral abnormalities were initially detected (Heffron et al 2009). However, more detailed analysis revealed a decreased proliferation of neural progenitor cells at E15.5 and E17.5 resulting in a reduced number of astroglial cells, and thinning of cortical layers II/III.…”