Abstract
The Dmp1-Cre mouse, expressing Cre from an 8-kb DNA fragment of the mouse Dmp1 gene, is a common tool to study gene functions in osteocytes. Here we report that the deletion of Tsc1 (TSC complex subunit 1) by 8 kb Dmp1-Cre causes rectal prolapse in mice. Histological examination shows the presence of colon polyps in Tsc1-deficient mice in association with significantly larger colon and narrower lumen, which recapitulates the common polyps pathology in Tuberous Sclerosis, an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. The intestine in Tsc1-deficient mice is also enlarged with the presence of taller villi. Using the Ai14 reporter mice that express a red fluorescence protein upon Cre recombination, we show that 8 kb Dmp1-Cre activity is evident in portion of the mesenchyme of the colon and small intestine. Lastly, our data show that Tsc1 deletion by Dmp1-Cre leads to an increased proliferation in the mesenchyme of colon, which at least partly contributes to the polyps pathology seen in this mouse model and is likely a contributing factor of the polyps in Tuberous Sclerosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, Rhee Y, Bellido T, Plotkin LI (2012) Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 27:374–389
Choi HK, Yuan H, Fang F, Wei X, Liu L, Li Q, Guan JL, Liu F (2018) Tsc1 regulates the balance between osteoblast and adipocyte differentiation through Autophagy/Notch1/beta-Catenin Cascade. J Bone Miner Res 33:2021–2034
Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356
Dallas SL, Xie Y, Shiflett LA, Ueki Y (2018) Mouse cre models for the study of Bone Diseases. Curr Osteoporos Rep 16:466–477
Deng Z, Lei X, Zhang X, Zhang H, Liu S, Chen Q, Hu H, Wang X, Ning L, Cao Y, Zhao T, Zhou J, Chen T, Duan E (2015) mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration. J Mol Cell Biol 7:62–72
Elmaci I, Altinoz MA, Sari R, Bolukbasi FH (2018) Phosphorylated histone H3 (PHH3) as a novel cell proliferation marker and prognosticator for meningeal tumors: a short review. Appl Immunohistochem Mol Morphol 26:627–631
Fang F, Sun S, Wang L, Guan JL, Giovannini M, Zhu Y, Liu F (2015a) Neural crest-specific TSC1 deletion in mice leads to sclerotic craniofacial bone lesion. J Bone Miner Res 30:1195–1205
Fang F, Wei X, Hu M, Liu F (2015b) A mouse model of craniofacial bone lesion of tuberous sclerosis complex. Musculoskelet Regen 1:e814
Feng JQ, Huang H, Lu Y, Ye L, Xie Y, Tsutsui TW, Kunieda T, Castranio T, Scott G, Bonewald LB, Mishina Y (2003) The dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J Dent Res 82:776–780
George A, Sabsay B, Simonian PA, Veis A (1993) Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J Biol Chem 268:12624–12630
Gould SR (1991) Hamartomatous rectal polyps are common in tuberous sclerosis. Ann N Y Acad Sci 615:71–80
Hsieh YL, Wei X, Wang Y, Zhang H, Qi S, Xie D, Mishina Y, Mendonca D, Hatch N, Liu F (2021) Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses. Bone 153:116142
Kalajzic I, Braut A, Guo D, Jiang X, Kronenberg MS, Mina M, Harris MA, Harris SE, Rowe DW (2004) Dentin matrix protein 1 expression during osteoblastic differentiation, generation of an osteocyte GFP-transgene. Bone 35:74–82
Kalajzic I, Matthews BG, Torreggiani E, Harris MA, Divieti Pajevic P, Harris SE (2013) In vitro and in vivo approaches to study osteocyte biology. Bone 54:296–306
Kwiatkowski DJ, Manning BD (2005) Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 14 Spec No 2:R251–258
Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11:525–534
Lim J, Burclaff J, He G, Mills JC, Long F (2017) Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice. Bone Res 5:16049
Liu W, Wang Z, Yang J, Wang Y, Li K, Huang B, Yan B, Wang T, Li M, Zou Z, Yang J, Xiao G, Cui ZK, Liu A, Bai X (2019) Osteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice. Open Biol 9:180262
Lu Y, Zhang S, Xie Y, Pi Y, Feng JQ (2005) Differential regulation of dentin matrix protein 1 expression during odontogenesis. Cells Tissues Organs 181:241–247
Lu Y, Xie Y, Zhang S, Dusevich V, Bonewald LF, Feng JQ (2007) DMP1-targeted cre expression in odontoblasts and osteocytes. J Dent Res 86:320–325
Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, Lein ES, Zeng H (2010) A robust and high-throughput cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13:133–140
Terasawa M, Shimokawa R, Terashima T, Ohya K, Takagi Y, Shimokawa H (2004) Expression of dentin matrix protein 1 (DMP1) in nonmineralized tissues. J Bone Miner Metab 22:430–438
Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N, Komori T (2001) Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. J Bone Miner Res 16:2017–2026
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ghassib, I., Zhang, H., Qi, S. et al. Off-target activity of the 8 kb Dmp1-Cre results in the deletion of Tsc1 gene in mouse intestinal mesenchyme. Transgenic Res 32, 135–141 (2023). https://doi.org/10.1007/s11248-022-00332-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11248-022-00332-8