Collagens in the developing and diseased nervous system

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.).

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“…37 There is growing awareness of roles for a diversity of collagens in central nervous system development. 50 …”

Section: Collagen Gene Expression In the Cns: Up-regulation In Reactimentioning

confidence: 99%

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

Heffron

Landreth

Samuels

et al. 2009

The American Journal of Pathology

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“…RNA for soluble neuron growth factors, including glial cell derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophins-3(NT-3) were found to be expressed in corneal stromal and epithelial tissue[10]. Insoluble extracellular matrix (ECM) components including collagen types I, V, VI were also secreted by corneal resident cells, which ultimately modulated neuronal outgrowth [13, 14]. In vitro models of neuron interactions with corneal cells would provide a tool to study the role of ECM and soluble factors on neuronal extension and organization.…”

Section: Introductionmentioning

confidence: 99%

Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds

Wang

Ghezzi

White

et al. 2015

J. Biomed. Mater. Res.

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Corneal tissue displays the highest peripheral nerve density in the human body. Engineering of biomaterials to promote interactions between neurons and corneal tissue could provide tissue models for nerve/cornea development, platforms for drug screening, as well as innovative opportunities to regenerate cornea tissue. The focus of this study was to develop a co-culture system for differentiated human corneal stromal stem cells (dhCSSCs) and dorsal root ganglion neurons (DRG) to mimic the human cornea tissue interactions. Axon extension, connectivity, and neuron cell viability were studied. DRG neurons developed longer axons when co-cultured with dhCSSCs in comparison to neuron cultures alone. To assess the mechanism involved in the co-culture response, nerve growth factors secreted by dhCSSCs including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and Neurotrophin-3 (NT-3) were characterized with greater focus on BDNF secretion. DhCSSCs also secreted collagen type I, an extracellular matrix molecule favorable for neuronal outgrowth. This co-culture system provides a slowly degrading silk matrix to study neuronal responses in concert with hCSSCs related to innervation of corneal tissue with utility towards human corneal nerve regeneration and associated diseases.

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“…Col IV and laminin are present in the basement membrane and have been implicated in development of the neuromuscular junction and in axonal growth (Hubert et al, 2008). They are also present in fractones, extravascular basal lamina structures involved in neurogenesis during both development and adulthood (Kerever et al, 2007).…”

mentioning

confidence: 99%

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

Uemura

Refaat

Shinoyama

et al. 2009

J of Neuroscience Research

140

128

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Cell replacement therapy holds great promise as a means of treating neurological disorders, including Parkinson's disease. However, one of the major obstacles to the success of this treatment is the low survival rate of grafted cells, which probably results from mechanical damage, acute inflammation, and immunological rejection. To overcome this problem, we investigated the effect of different types of extracellular matrix (ECM) on the survival and differentiation of embryonic stem (ES) cell-derived neural precursor cells (NPCs). We tested materials from natural sources, including collagen, ornithine/laminin, and growth factor-reduced Matrigel (gfrMG), as well as the synthetic biomaterial PuraMatrix, which consists of self-assembling polypeptides. GfrMG efficiently supported cell survival, migration, and neurite outgrowth in vitro and promoted proliferation of grafted cells in vivo, resulting in larger graft volume and an increase in the number of TH-positive dopaminergic neurons in the graft. GfrMG did not induce dopaminergic differentiation directly; rather, it reduced the invasion of pan-leukocytic CD45-positive cells into the graft. Insofar as the inflammatory or immune response in the host brain inhibits neuronal differentiation of grafted NPCs, gfrMG may increase the number of TH-positive cells by suppressing this effect. Thus, gfrMG appears to provide a suitable scaffold that supports survival and differentiation of NPCs. However, because it is derived from mouse sarcomas, a human-derived matrix or synthetic biomaterial must be developed for clinical applications.

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Collagens in the developing and diseased nervous system

Cited by 105 publications

References 146 publications

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

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

Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

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