Gremlin 1 — small protein, big impact: the multiorgan consequences of disrupted BMP antagonism^†

Abstract

Highly conserved, complex and interacting morphogen signalling pathways regulate adult stem cells and control cell fate determination across numerous different organs. In homeostasis, the bone morphogenetic protein (BMP) pathway predominantly promotes cell differentiation. Localised expression of ligand sequestering BMP antagonists, such as Gremlin 1 (Grem1), necessarily restricts BMP activity within the stem cell niche and facilitate stemness and selfrenewal. In a new paper, Rowan, Jahns et al show that acute deletion of Grem1 in adult mice, using a ubiquitous ROSA26-Cre recombinase, induced not only severe intestinal enteropathy but also hypocellular bone marrow failure suggestive of stem cell niche collapse in both tissues. Grem1 has an increasingly recognised pleiotrophic role in a number of organ systems and is implicated across a wide range of disease states. Although the importance of Grem1 in intestinal stem cell regulation has been well described, a putative function in haematopoietic niche maintenance is novel and requires further exploration. Moreover, the complex and context-specific regulation of Grem1, among a host of functionally convergent but structurally disparate BMP antagonists, warrants further research as we learn more about the pathogenic consequences of deranged expression of this small, but important, protein.

Irradiation and lithium treatment alter the global DNA methylation pattern and gene expression underlying a shift from gliogenesis towards neurogenesis in human neural progenitors

“…BMP4 is a positive regulator, while SMAD7 (intracellular) and gremlin1 (extracellular) are negative regulators of the BMP pathway 49 . Inhibition of the BMP pathway through gremlin1 binding to BMPs has been shown to promote neuronal speci cation 50,51 . In this study on human neural progenitors, we observed increased GREM1 expression in the irradiated and LiCl treated group (Fig.…”

GREM1 signaling in cancer: tumor promotor and suppressor?

“…Highly selective gene deletion of GREM1 using CRISPR/Cas9 techniques, or its predicted binding partners will address some of the issues regarding the pathophysiological significance of these interactions. However, care needs to be taken in interpreting data from transgenic/knockout mice using diverse CRE recombinase constructs and purported tissue-specific promotors that may lead to off-target effects (Gooding and Leedham 2020 ). Moreover, CRISPR/Cas9 techniques can be used to epitope tag GREM1 or its binding partners and allow for endogenous protein interaction studies, for example using sensitive BioID proximity labelling methods in which the bait protein is fused to a promiscuous biotin ligase (Rosenthal et al 2021 ).…”