Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Abstract

Gene-targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4 -5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed-effects model to fit the growth data of wild-type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates.

AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein

“…In addition, among the biological functions, "skeletal development," "cellular signaling," and "communication" were enriched. These findings are in line with the skeletal deformations observed in GRG5 knockout mice 17 and the proposed functions of AES as an enhancer of Wnt signaling. The enriched molecular processes For personal use only.…”

“…22 AES has also been demonstrated to interact with other transcription factors. For example, Wang et al 17 have demonstrated a positive regulation of RUNX function by a dominant negative variant of GRG5, whereas GRG3 inhibits the RUNX2 function required for murine skeletal development and postnatal growth. 17 Thus, regulating the inhibitor of TLE-repressors might be a fine-tuned process that is altered in AML.…”

“…17 Animal experiments were approved and performed in accordance with all regulatory guidelines. For all clinical patient samples, informed consent was obtained in accordance with the Declaration of Helsinki, and the study was approved by the Ethics committee.…”

Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer

“…These results are inconsistent with those of previous studies, demonstrating that activated Notch signaling facilitates tumor formation in Apc min mice through increased proliferation of tumor cells (10,11). Other studies have also reported that Aes can modulate other signaling pathways, such as WNT, TGF-β, and Hedgehog, which have critical roles in CRCs (40)(41)(42). Therefore, further characterization to determine whether Aes affects CRCs through Notch or other signaling pathways is required.…”

Wnt9a signaling is required for joint integrity and regulation ofIhhduring chondrogenesis

“…Groucho 5 (Grg5; Aes -Mouse Genome Informatics) acts as a derepressor in ␤-catenin/TCF signaling, unlike groucho 1-4, which act as co-repressors (Brantjes et al, 2001). Intriguingly, Grg5 -/-mice display a postnatal, temporary reduction in Ihh expression, which is further dependent on Runx2 levels (Wang et al, 2004;Wang et al, 2002). Thus, it is conceivable that the ␤-catenin/Lef1 complex and Runx2 could cooperatively regulate Ihh.…”