Noggin is a secreted homodimeric glycoprotein that is an antagonist of bone morphogenetic proteins (BMPs). Mature Human Noggin contains an N-terminal acidic region; a central basic heparin-binding segment and a C-terminal cysteine-knot structure. Noggin is very highly conserved among vertebrates; such that mature human Noggin shares 99%; 99%; 98%; 97% and 89% aa sequence identity with mouse; rat bovine; equine and chicken Noggin; respectively. Secreted Noggin probably remains close to the cell surface due to its binding of heparin-containing proteoglycans. Noggin binds some BMPs such as BMP4 with high affinity and others such as BMP7 with lower affinity. It antagonizes BMP bioactivities by blocking epitopes on BMPs that are needed for binding to both type I and type II receptors. Noggin is expressed in defined areas of the adult central nervous system and peripheral tissues such as lung; skeletal muscle and skin. During culture of human embryonic stem cells (hESC) or neural stem cells under certain conditions; addition of Noggin to antagonize BMP activity may allow stem cells to proliferate while maintaining their undifferentiated state; or alternatively; to differentiate into dopaminergic neurons.
Noggin is a secreted protein involved at multiple stages of vertebrate embryonic development including neural induction and is known to exert its effects by inhibiting the bone morphogenetic protein (BMP)-signaling pathway. It binds several BMPs with very high (picomolar) affinities; with a marked preference for BMP2 and BMP4 over BMP7. By binding tightly to BMPs; Noggin prevents BMPs from binding their receptors. Noggin binds the bone morphogenetic proteins (BMP) such as BMP-4 and BMP-7; and inhibits BMP signaling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. Interaction of BMP and its antagonist Noggin governs various developmental and cellular processes; including embryonic dorsal-ventral axis; induction of neural tissue; formation of joints in the skeletal system and neurogenesis in the adult brain. Noggin plays a key role in neural induction by inhibiting BMP4; along with other TGF-β signaling inhibitors such as chordin and follistatin. Mouse knockout experiments have demonstrated that noggin also plays a crucial role in bone development; joint formation; and neural tube fusion.
Reticulon 4 receptor (RTN4R), also known as Nogo-66 Receptor (NgR), is a glycosylphosphoinositol (GPI)-anchored protein that belongs to the Nogo recptor family including three members. Mouse RTN4R cDNA contains 10 LRP (Leucine-rich) repeats. RTN4R is expressed predominantly in neurons and their axons in the central nervous systems (CNS). As a receptor for myelin-derived proteins Nogo, myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (OMG), RTN4R mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult CNS. It has been shown that RTN4R performs its inhibitory actions by interacting with the p75 neurotrophin receptor (p75NTR), a TNFRSF member also known for modulating the activities of the Trk family and for inducing apoptosis in neurons and oligodendrocytes. RTN4R may be proposed as a potential drug target for treatment of various neurological conditions such as spinal cord injury, CNS lesions, peripheral nerve injury, stroke and Alzheimer's disease (AD). Additionally, RTN4R may play a role in regulating the function of the gap junctions.
Nogo Receptor (NgR) is a glycosylphosphoinositol (GPI)-anchored protein that belongs to the Nogo recptor family. Human NgR is predominantly expressed in neurons and their axons in the central nervous systems. As a receptor for myelin-derived proteins Nogo; myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (OMG); NgR mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system. NgR may be proposed as a potential drug target for treatment of various neurological conditions. Additionally; NgR may play a role in regulating the function of gap junctions.
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