Publications by authors named "Oscar Cazares"

5 Publications

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SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal.

Dev Cell 2022 03 23;57(5):624-637.e4. Epub 2022 Feb 23.

Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal.
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http://dx.doi.org/10.1016/j.devcel.2022.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974236PMC
March 2022

Alveolar progenitor differentiation and lactation depends on paracrine inhibition of notch via ROBO1/CTNNB1/JAG1.

Development 2021 11 10;148(21). Epub 2021 Nov 10.

Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA 95064, USA.

In the mammary gland, how alveolar progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation in mouse. Loss of Robo1 in the mammary gland epithelium activates Notch signaling, which expands the alveolar progenitor cell population at the expense of alveolar differentiation, resulting in compromised lactation. ROBO1 is expressed in both luminal and basal cells, but loss of Robo1 in basal cells results in the luminal differentiation defect. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 by regulating β-catenin (CTNNB1), which binds the Jag1 promoter. Together, our studies reveal how ROBO1/CTTNB1/JAG1 signaling in the basal compartment exerts paracrine control of Notch signaling in the luminal compartment to regulate alveolar differentiation during pregnancy.
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http://dx.doi.org/10.1242/dev.199940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627605PMC
November 2021

Salivary gland: A budding genius.

Dev Cell 2021 08;56(16):2271-2272

Program in Craniofacial Biology and Division of Craniofacial Anomalies, Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA; Division of Medical Genetics, Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Electronic address:

During salivary gland development, branches arise through formation of new end buds (budding) and division of existing buds (clefting). In a recent Cell study, Wang et al., (2021) report that mouse salivary gland budding is reliant on a delicate interplay between epithelial cells and the extracellular matrix surrounding them.
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http://dx.doi.org/10.1016/j.devcel.2021.08.001DOI Listing
August 2021

Generation of Mosaic Mammary Organoids by Differential Trypsinization.

J Vis Exp 2020 03 11(157). Epub 2020 Mar 11.

Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz;

Organoids offer self-organizing, three-dimensional tissue structures that recapitulate physiological processes in the convenience of a dish. The murine mammary gland is composed of two distinct epithelial cell compartments, serving different functions: the outer, contractile myoepithelial compartment and the inner, secretory luminal compartment. Here, we describe a method by which the cells comprising these compartments are isolated and then combined to investigate their individual lineage contributions to mammary gland morphogenesis and differentiation. The method is simple and efficient and does not require sophisticated separation technologies such as fluorescence activated cell sorting. Instead, we harvest and enzymatically digest the tissue, seed the epithelium on adherent tissue culture dishes, and then use differential trypsinization to separate myoepithelial from luminal cells with ~90% purity. The cells are then plated in an extracellular matrix where they organize into bilayered, three-dimensional (3D) organoids that can be differentiated to produce milk after 10 days in culture. To test the effects of genetic mutations, cells can be harvested from wild type or genetically engineered mouse models, or they can be genetically manipulated prior to 3D culture. This technique can be used to generate mosaic organoids that allow investigation of gene function specifically in the luminal or myoepithelial compartment.
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http://dx.doi.org/10.3791/60742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656113PMC
March 2020

Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness.

J Cell Biol 2016 Mar;212(6):707-19

Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064

Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence.
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http://dx.doi.org/10.1083/jcb.201507054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792073PMC
March 2016
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