Munera, JO; Sundaram, N; Rankin, SA; Hill, D; Watson, C; Mahe, M; Vallance, JE; Shroyer, NR; Sinagoga, KL; Zarzoso-Lacoste, A; Hudson, JR; Howell, JC; Chatuvedi, P; Spence, JR; Shannon, JM; Zorn, AM; Helmrath, MA; Wells, JM. Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. Cell Stem Cell. 2017; 21(1):51-64.e6.
In this work we report the generation of human colonic organoids (HCOs) from pluripotent stem cells. To accomplish this we first found that a conserved BMP-HOX pathway requires establishing posterior identity in frog and mouse embryos. Then through temporal manipulation of the BMP signaling pathway during differentiation of human pluripotent stem cell we were able to generate HCOs. Transplantation and growth of HCOs in mice resulted in formation of human colonic tissue that was highly similar to human colon.
Wang, G; Gutzwiller, L; Li-Kroeger, D; Gebelein, B. A Hox complex activates and potentiates the Epidermal Growth Factor signaling pathway to specify Drosophila oenocytes. PLoS genetics. 2017; 13(7):e1006910-e1006910.
The highly conserved Hox transcription factors specify distinct cell fates along the body axis by regulating the expression of downstream genes and signaling pathways. For example, a Hox factor that is only expressed in the Drosophila abdomen (Abdominal-A) activates the release of a signaling molecule (epidermal growth factor, EGF) from a specific neural precursor cell. The induced cells that receive the signal become essential hepatocyte-like cells required for metabolism and animal growth. Here, we show that this same Hox factor is not only required for sending the EGF signal, but is also required within the hepatocyte-like cells to enhance the strength of the signal. Importantly, the thoracic Hox factor fails to both induce the signal and to enhance the signal, thereby providing a better understanding generation of these abdomen-specific cells and how distinct morphological structures become regionalized to specific segments of the embryo.
Adam, M; Potter, AS; Potter, SS. Psychrophilic proteases dramatically reduce single-cell RNA-seq artifacts: a molecular atlas of kidney development. Development (Cambridge). 2017; 144(19):3625-3632.
Single cell RNA seq is a powerful high resolution technology that is rapidly becoming a standard tool for analysis. The first step is generally an enzymatic dissociation of tissue at 37OC to create a single cell suspension. During this dissociation process the cells of interest are undergoing artifact changes in gene expression. In this publication we show that it is possible to carry out the tissue dissociation in the cold, using proteases from psychrophilic organisms that adapt to live in the cold, thereby significantly reducing gene expression artifacts.
Kuerbitz, J; Arnett, M; Ehrman, S; Williams, MT; Vorhees, CV; Fisher, SE; Garratt, AN; Muglia, LJ; Waclaw, RR; Campbell, K. Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2018; 38(5):1160-1177.
This study demonstrates a requirement for the transcription factor Tshz1 in the generation of intercalated cells (ITCs) of the amygdala. These neurons represent a nodal point for incoming cortical information and output form the central amygdala and show implication in the correct processing of fear responses. By analyzing the Tshz1 mutants, which lack normal ITCs, we found that not only were fear responses altered but we also observed depression-like behaviors as well as impaired social interactions. Thus our study implicates altered ITC function in affective disorders.
Volovelsky, O; Nguyen, T; Jarmas, AE; Combes, AN; Wilson, SB; Little, MH; Witte, DP; Brunskill, EE; Kopan, R. Hamartin regulates cessation of mouse nephrogenesis independently of Mtor. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(23):5998-6003.
Most of us are born with about 1 million nephrons, all of which form in the womb between weeks 25 to 36 of gestation. Unfortunately, there can be an interruptions of the nephron formation process when babies are born preterm, which places them at higher risk of developing kidney disease later in life. We are trying to understand the genetic determinants and the mechanisms regulating nephron numbers. This study reveals one mechanism involved in in this regulation. The discovery, based on mouse models, points to a unknown function of a known gene and suggests that intervention during pregnancy or after preterm birth might extend nephron development. If translated to clinical practice years from now, the result could mean a reduced need for kidney transplants and fewer deaths from kidney disease.