Biology subjects

Munoz-Nava, L. M.

Publications and source records attributed to Munoz-Nava, L. M..

4 recordsLinked to original sources

bioRxiv2026

EGF and EREG regulate early oncoprotein-mediated tissue transformation in intestinal organoids.

Somatic mutations, coupled with abnormal extracellular signaling cues, promote tumor development. The abundance and affinity of EGF-family ligands for EGFR influence tissue development and play a central role in organoid culture by differentially regulating the balance between crypt proliferation and villus differentiation in mouse small intestinal organoids (mSIOs). To test how medium ligand composition affects early oncogenic transformation, we generated a Ptprg KO organoid line by CRISPR/Cas9 and two previously described organoid lines harboring synthetic bio-orthogonal expression systems for KRASG12V and {beta}-Ctn4A, activated by the membrane-diffusible ligands TMP or TMP-Cl. Measurements of crypt and villus region area showed that acute oncogenic activity did not alter organoid growth in media containing 50 ng/mL EGF; however, organoids grown without EGF consistently showed differential growth of the crypt region. Furthermore, EREG and sub-saturating EGF (0.5-5 ng/mL) treatments differentially affected crypt/villus development in each organoid line. Finally, we measured organoid morphology and found that crypt domain spatial distribution is independent of crypt area and requires EGF or EREG, highlighting the role of both proliferation and crypt organization in oncogenic tissue transformation.

cancer biology↗

bioRxiv2026

Proliferation and differentiation in intestinal organoids as a balance of ligand-modulated the EGFR trafficking

Epidermal Growth factor (EGF) signaling is associated with (oncogenic) proliferation. Conversely, EGF-family ligands are able to trigger a differentiation program in cultured cells, an effect attributed to ligand affinity and EGFR phosphorylation. How EGF/EGFR driven proliferation-differentiation dynamics underlie tissue self-renewal has not been addressed. We show that culturing mouse small intestinal organoids (mSIOs) without EGF enhanced EGFR expression and base phosphorylation while maintaining a balanced development of proliferative crypts and differentiated villi. Addition of EGF or EREG triggers receptor endocytosis, reducing cell-surface and expression levels. While EGF promoted crypt proliferation, EREG promoted both proliferation and villus differentiation compared to untreated controls. Removal or re-introduction of EGF or EREG proved sufficient to induce development comparable to constant presence of ligands over 96h. Sub-saturating concentrations of EGF led to increased villus differentiation, resembling EREG treatments, suggesting that control over EGFR endocytic cycle ultimately regulates the balance of proliferation and differentiation in mSIOs SummaryExpression and signaling competency at the plasma membrane of EGFR drives crypt proliferation vs villus differentiation by medium ligand-composition, aiding mouse intestinal organoids self-renewal and regeneration.

developmental biology↗

bioRxiv2022

Vestigial-dependent recruitment contributes to robust patterning but is not required for wing-fate induction in Drosophila

Cell recruitment is a process by which a differentiated cell induces neighboring cells to adopt its same cell fate. In Drosophila, cells expressing the wing selector gene, vestigial (vg), drive a feed-forward recruitment signal that propagates Vg expression suggesting that the Vg pattern is established as a wavefront throughout the wing pouch. However, the dynamics of Vg pattern formation does not meet this expectation. Here we show that an induction signal may drive Vg expression without Vg feedforward recruitment several cells away from the dorsal-ventral (DV) boundary. Particularly, when Vg expression is strongly inhibited either at the DV boundary or away from it, the activation of the vg Quadrant Enhancer still occurs at a distance, although the levels and precision of the pattern are compromised. Using live imaging of a dual-fluorescent reporter system, we show that contact-dependent cell recruitment does occur in wild-type conditions suggesting that a combination of a long-range induction signal and a signal-relay recruitment establishes Vg patterning in a robust manner. Overall, our findings reveal a previously unidentified role of cell recruitment as a robustness-conferring patterning mechanism. Summary StatementRobust formation of the Vg pattern is established by two mechanisms: a fast, long-range, but noisy induction signal; and a more precise signal relay, contact-dependent, cell recruitment process.

developmental biology↗

bioRxiv2021

Interplay between cell proliferation and recruitment controls the duration of growth and final size of the Drosophila wing

How organs robustly attain a final size despite perturbations in cell growth and proliferation rates is a fundamental question in developmental biology. Since organ growth is an exponential process driven mainly by cell proliferation, even small variations in cell proliferation rates, when integrated over a relatively long time, will lead to large differences in size, unless intrinsic control mechanisms compensate for these variations. Here we use a mathematical model to consider the hypothesis that in the developing wing of Drosophila, cell recruitment, a process in which undifferentiated neighboring cells are incorporated into the wing primordium, determines the time in which growth is arrested in this system. Under this assumption, our model shows that perturbations in proliferation rates of wing-committed cells are compensated by an inversely proportional duration of growth. This mechanism ensures that the final size of the wing is robust in a range of cell proliferation rates. Furthermore, we predict that growth control is lost when fluctuations in cell proliferation affects both wing-committed and recruitable cells. Our model suggests that cell recruitment may act as a temporal controller of growth to buffer fluctuations in cell proliferation rates, offering a solution to a long-standing problem in the field. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/444212v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@13b7947org.highwire.dtl.DTLVardef@1973142org.highwire.dtl.DTLVardef@122ec0dorg.highwire.dtl.DTLVardef@1b7513e_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗