Gremlin1, previously known as Drm, is a highly conserved 20.7-kDa, 184 amino acid
glycoprotein part of the DAN family and is a cysteine knot-secreted protein.[1][2] Gremlin1 was first identified in differential screening as a transcriptional down-regulated gene in v-mos-transformed rat embryonic fibroblasts.[3]
Function
Gremlin1 (Grem1) is known for its antagonistic interaction with
bone morphogenetic proteins (BMPs) in the
TGF beta signaling pathway. Grem1 inhibits predominantly
BMP2 and
BMP4 in limb buds and functions as part of a self-regulatory feedback signaling system, which is essential for normal limb bud development and digit formation.[4][5][6] Inhibition of BMPs by Grem1 in limb buds allows the transcriptional up-regulation of the
fibroblast growth factors (FGFs) 4 and 8 and
sonic hedgehog (SHH) ligands, which are part of the signaling system that controls progression of limb bud development.[7][8] Grem1 regulation of BMP4 in mice embryos is also essential for kidney and lung branching
morphogenesis.[9][10]
Fetal Development
While GREM1 functions as a BMP antagonist during limb bud formation, it also functions as a pro-angiogenic molecule. As stated above, GREM1 is a member of the cysteine-knot superfamily similar to
vascular endothelial growth factor (VEGF). Both molecules are capable of binding to the VEGF receptor to activate vascular differentiation and proliferation during development.[11] In the absence of GREM1, it is possible to see unregulated bone growth as there is no inhibitory signal to regulate the bone morphogenetic proteins. Gremlin1 also plays a role in the
epithelial-mesenchymal transition (EMT). Although this is an important process for neural tube development and other fetal structures, it is also a necessary process for tumor metastasis as it can activate the TGF beta pathway in the event of an overexpression of GREM1. This has made GREM1 the proposed target for cancer therapeutics, however, more research is necessary before any major steps are taken. [12]
Clinical significance
Cancer
Data from
microarrays of cancer and non-cancer tissues suggest that grem1 and other
BMPantagonists are important in the survival of cancer
stroma and proliferation in some cancers.[13] Grem1 expression is found in many cancers and is thought to play important roles in uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and
sarcomacarcinomas. More specifically, the Grem1
binding site (between residues 1 to 67) interacts with the
binding proteinYWHAH, (whose binding site for Grem1 is between residues 61-80) and is seen as a potential therapeutic and diagnostic target against human cancers.[3]
Grem1 also plays a BMP-dependent role in
angiogenesis on
endothelium of human lung tissue, which implies a role for Grem1 in the development of cancer.[2]
Bone
Deletion of Grem1 in mice after birth increased bone formation and increased
trabecular bone volume, whereas overexpression causes inhibition of bone formation and
osteopenia.[1][14] Conditional deletion of one copy of Grem1 does not produce an abnormal phenotype and deletion of both copies causes only a small difference in phenotype in one-month-old male mice, but this difference cannot be observed after 3 months of age.[14]
Grem1 plays an important role in
bone development and a lesser known function later in adulthood. Overexpression of Grem1 decreases
osteoblastdifferentiation or the inhibition of bone formation and the ability for
bone remodeling.[1] In addition, overexpression of Grem1 in the mouse limb bud inhibits BMP signaling which can lead to digit loss as well as
polydactyly.[15] Overexpression of grem1 in stromal and osteoblastic cells in addition to the inhibition of BMP, grem 1 inhibits activation of Wnt/
β-catenin signaling activity. The interaction between Grem1 and the
Wnt signaling pathway is not fully understood.[14]
Transcriptional regulation
Cis-regulatory modules (CRMs) regulate when and where Grem1 is transcribed. It has been reported that a CRM acts as both a silencer and activator for Grem1 transcription in the mouse limb bud.[16] There are additional CRMs that regulate Grem1 transcription.[17]
^Bénazet JD, Bischofberger M, Tiecke E, Gonçalves A, Martin JF, Zuniga A, Naef F, Zeller R (2009). "A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning". Science. 323 (5917): 1050–3.
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^Khokha MK, Hsu D, Brunet LJ, Dionne MS, Harland RM (2003). "Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning". Nat. Genet. 34 (3): 303–7.
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^Michos O, Gonçalves A, Lopez-Rios J, Tiecke E, Naillat F, Beier K, Galli A, Vainio S, Zeller R (2007). "Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis". Development. 134 (13): 2397–405.
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^Shi W, Zhao J, Anderson KD, Warburton D (2001). "Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis". Am. J. Physiol. Lung Cell Mol. Physiol. 280 (5): L1030–9.
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^Jacqueline L. Norrie, Jordan P. Lewandowski, Cortney M. Bouldin, Smita Amarnath, Qiang Li, Martha S. Vokes, Lauren I.R. Ehrlich, Brian D. Harfe, Steven A. Vokes. Dynamics of BMP signaling in limb bud mesenchyme and polydactyly (2014) Developmental Biology Volume 393, Issue 2, Pages 270–281
^Li, Q., Lewandowski, J. P., Powell, M. B., Norrie, J. L., Cho, S. H. and Vokes, S. a (2014). A Gli silencer is required for robust repression of gremlin in the vertebrate limb bud. Development 141, 1906–14
^Zuniga, A., Laurent, F., Lopez-Rios, J., Klasen, C., Matt, N. and Zeller, R. (2012). Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1 expression in mouse limb buds. BMC Dev. Biol. 12, 23