Tutkijat luonnehtivat uuden Kelch proteiinin joka on KLHL1 kaltainen ja Mayvenin sukuinen MPR2. Se osoittautuu tärkeäksi merkitsijäksi oligodenrosyyttien elämässä.
Process Elongation of Oligodendrocytes Is Promoted by the Kelch-related Protein MRP2/KLHL1*
Shuxian Jiang1,
Seyha Seng1,
Hava Karsenty Avraham,
Yigong Fu and
Shalom Avraham2
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115
- ↵2 To whom correspondence should be addressed: 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-667-0063; Fax: 617-975-6373 or 617-975-5240; E-mail: savraham{at}bidmc.harvard.edu.
Oligodendrocytes (OLGs) are generated by
progenitor cells that are committed to differentiating into
myelin-forming cells
of the central nervous system. Rearrangement of the
cytoskeleton leading to the extension of cellular processes is
essential
for the myelination of axons by OLGs. Here, we have
characterized a new member of the Kelch-related protein family termed
MRP2 (for Mayven-related protein 2) that is
specifically expressed in brain. MRP2/KLHL1 is expressed in
oligodendrocyte precursors
and mature OLGs, and its expression is up-regulated
during OLG differentiation. MRP2/KLHL1 expression was abundant during
the specific stages of oligodendrocyte development,
as identified by A2B5-, O4-, and O1-specific oligodendrocyte markers.
MRP2/KLHL1 was localized in the cytoplasm and along
the cell processes. Moreover, a direct endogenous association of
MRP2/KLHL1
with actin was observed, which was significantly
increased in differentiated OLGs compared with undifferentiated OLGs.
Overexpression
of MRP2/KLHL1 resulted in a significant increase in
the process extension of rat OLGs, whereas MRP2/KLHL1 antisense reduced
the process length of primary rat OLGs.
Furthermore, murine OLGs isolated from MRP2/KLHL1 transgenic mice showed
a significant
increase in the process extension of OLGs compared
with control wild-type murine OLGs. These studies provide insights into
the role of MRP2/KLHL1, through its interaction
with actin, in the process elongation of OLGs.
Oligodendrocytes (OLGs)3
are a major cell type in the central nervous system. Development of
these cells is necessary for normal functioning of the
brain, and injury to them is involved in the
pathogenesis of important neurological disorders including cerebral
palsy, multiple
sclerosis, and periventricular leukomalacia (1, 2). OLGs represent the myelin-forming cells of the central nervous system. They produce numerous membranous processes, which
spirally enwrap neuronal axons, forming multilamellar myelin sheaths (3, 4). OLGs are metabolically the most active cells in the brain (5). Before OLGs can remyelinate, they must first be able to extend their processes, and contact the demyelinated axons. However,
the molecules involved in the mechanisms of OLG process extension are poorly defined.
A new and unique family of actin-binding proteins with sequences and domains homologous with the Drosophila “Kelch” protein has emerged (6). Kelch protein is believed to be important for the maintenance of the ordered cytoskeleton (7, 8). The Kelch protein has two structural domains that are also found in other molecules. The first domain, which consists of
about 115 amino acids, has been named the BTB (Bric-a-brac, Tramtrack, Broad-complex) domain (9) or POZ (Poxvirus zinc finger) domain (10).
The second domain, composed of about 50 amino acids repeated in tandem,
has been called the “Kelch repeats.” The BTB/POZ
domain has been proposed to function as a
protein-protein interaction interface, which organizes higher order
structures involved
in chromatin folding or cytoskeleton organization (11).
The Kelch-related proteins are a
superfamily of proteins conserved in a wide range of organisms, from
viruses to mammals.
At least 60 Kelch-related proteins have been
identified, but their physiological and biochemical functions remain
largely
uncharacterized (12, 13). The Drosophila Kelch proteins colocalize with actin filaments in a structure called the ring canal, which bridges 15 nurse cells and the
oocyte. Drosophila Kelch protein plays an important role in maintaining actin organization during the development of ring canals (6, 8).
The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15).
The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15).
We have previously identified and characterized two actinbinding proteins, termed NRP/B/ENC-1 (KLHL37, PIG10 TP5310 ,5q13.3) (16-18) and Mayven (KHLH24q32.3) (19),
predominantly expressed in brain. Mayven is an actin-binding protein
that is co-localized with actin filaments in stress
fibers and in the patchy cortical actin-rich
regions of the cell margins and processes, including the process tips in
primary
neurons and U373-MG astrocytoma/glioblastoma cells (19).
During our study of proteins that are related to Mayven, we identified
and cloned a novel gene, which we termed: MRP2 (Mayven-related
protein 2) that was found to be identical to KLHL1 (20, 21).
In this study, we have investigated the expression of MRP2/KLHL1 in
OLGs and its possible role in the dynamics of cytoskeletal
rearrangement, leading to the elongation of OLG
processes.
Oligodendrocytes (OLGs)3
are a major cell type in the central nervous system. Development of
these cells is necessary for normal functioning of the
brain, and injury to them is involved in the
pathogenesis of important neurological disorders including cerebral
palsy, multiple
sclerosis, and periventricular leukomalacia (1, 2). OLGs represent the myelin-forming cells of the central nervous system. They produce numerous membranous processes, which
spirally enwrap neuronal axons, forming multilamellar myelin sheaths (3, 4). OLGs are metabolically the most active cells in the brain (5). Before OLGs can remyelinate, they must first be able to extend their processes, and contact the demyelinated axons. However,
the molecules involved in the mechanisms of OLG process extension are poorly defined.
A new and unique family of actin-binding proteins with sequences and domains homologous with the Drosophila “Kelch” protein has emerged (6). Kelch protein is believed to be important for the maintenance of the ordered cytoskeleton (7, 8). The Kelch protein has two structural domains that are also found in other molecules. The first domain, which consists of
about 115 amino acids, has been named the BTB (Bric-a-brac, Tramtrack, Broad-complex) domain (9) or POZ (Poxvirus zinc finger) domain (10).
The second domain, composed of about 50 amino acids repeated in tandem,
has been called the “Kelch repeats.” The BTB/POZ
domain has been proposed to function as a
protein-protein interaction interface, which organizes higher order
structures involved
in chromatin folding or cytoskeleton organization (11).
The Kelch-related proteins are a
superfamily of proteins conserved in a wide range of organisms, from
viruses to mammals.
At least 60 Kelch-related proteins have been
identified, but their physiological and biochemical functions remain
largely
uncharacterized (12, 13). The Drosophila Kelch proteins colocalize with actin filaments in a structure called the ring canal, which bridges 15 nurse cells and the
oocyte. Drosophila Kelch protein plays an important role in maintaining actin organization during the development of ring canals (6, 8). The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function
in multiprotein complexes through contact sites in their β-propeller domains (14).
Recently, a new member of the BTB/Kelch repeat family, gigaxonin, was
reported to be a pathological target for neurodegenerative
disorders in which alterations were found to
contain multiple mutations in the Kelch repeats in the neurofilament
network
(15).
We have previously identified and characterized two actinbinding proteins, termed NRP/B/ENC-1 (16-18) and Mayven (19),
predominantly expressed in brain. Mayven is an actin-binding protein
that is co-localized with actin filaments in stress
fibers and in the patchy cortical actin-rich
regions of the cell margins and processes, including the process tips in
primary
neurons and U373-MG astrocytoma/glioblastoma cells (19).
During our study of proteins that are related to Mayven, we identified
and cloned a novel gene, which we termed: MRP2 (Mayven-related
protein 2) that was found to be identical to KLHL1 (20, 21).
In this study, we have investigated the expression of MRP2/KLHL1 in
OLGs and its possible role in the dynamics of cytoskeletal
rearrangement, leading to the elongation of OLG
processes.
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