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Biology subjects

Zemper, A. E.

Publications and source records attributed to Zemper, A. E..

3 recordsLinked to original sources

The Role of Lrig1 in the Development of the Colonic Epithelium

Growth and specification of the mouse intestine occurs in utero and concludes after birth. While numerous studies have examined this developmental process in the small intestine, far less is known about the cellular and molecular cues required for colon development. In this study, we examine the morphological events leading to crypt formation, epithelial cell differentiation, areas of proliferation, and the emergence and expression of a stem and progenitor cell marker Lrig1. Through multicolor lineage tracing, we show Lrig1 expressing cells are present at birth and behave as stem cells to establish clonal crypts within three weeks after birth. In addition, we use an inducible knockout mouse to eliminate Lrig1 during colon development and show loss of Lrig1 restrains proliferation within a critical developmental time window, without impacting colonic epithelial cell differentiation. Our study illustrates the morphological changes that occur during crypt development and the importance of Lrig1 in the developing colon.

developmental biology↗

Lrig3 restricts the size of the colon stem cell compartment

The cellular census of the colonic crypt is tightly regulated, yet the molecular mechanisms that regulate this census are not fully understood. Lrig3, a transmembrane protein, is expressed in colonic crypt epithelial cells, including the stem, progenitor, and differentiated cell types. Mice missing Lrig3 have a disruption in their cellular census: using a novel Lrig3-/- mouse we demonstrate that Lrig3-/- mice have more cells per crypt, a greater mucosal area, and longer colons compared to wildtype mice, suggesting the expression of Lrig3 is required for both the total number of epithelial cells in the mouse colon, as well as colon length. In addition, we show Lrig3-/- mice have significantly more stem, progenitor, and deep crypt secretory cells, yet harbor a normal complement of enteroendocrine, Tuft, and absorptive cells. Lrig3-/- mice also have a concomitant decrease in phosphorylated Extracellular signal-related kinases, indicating the loss of Lrig3 leads to an expansion of the colonic stem cell compartment, in an Erk-dependent manner. Our study describes the expression of Lrig3 within the colon, defines perturbations in mice lacking Lrig3, and supports a role for Lrig3 in the establishment of both colonic crypt structure and cellular census, defined as the epithelial cell type and number in colon crypts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/483523v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@244c29org.highwire.dtl.DTLVardef@1045457org.highwire.dtl.DTLVardef@13d4134org.highwire.dtl.DTLVardef@83db4e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

Ablation of colonic epithelial Reg4+ support cells induces Notch-independent regeneration and mesenchymal remodeling.

The colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/478243v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@14ae224org.highwire.dtl.DTLVardef@144e18aorg.highwire.dtl.DTLVardef@13353aeorg.highwire.dtl.DTLVardef@badec4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗