The goal of this work is to understand the genetic and developmental underpinnings of organ morphogenesis. In this study, we focus on the problem of looping morphogenesis using the developing midgut as a model system. We previously demonstrated that the chirality of gut rotation (i.e. specification of its rotation in a counterclockwise direction) is mediated by changes in the cellular architecture of the dorsal mesentery. We have identified a number of transcription factors asymmetrically expressed in the dorsal mesentery. In the first Aim we will investigate the role each plays in changing the cellular organization within the mesentery as well as examining their cross regulation to understand the transcriptional network controlling this by first step of gut morphogenesis. In our second Aim we will turn our attention to the later steps of gut morphogenesis. We will examine how each subsequent coiling event relates to the initial decision to coil counter clockwise. We will examine the later roles of specific transcription factors in the process. And we will dissect the roles of physical forces and topological constraints in directing the formation of specific loops during midgut organogenesis.

Public Health Relevance

We are studying looping morphogenesis of the gut. Failure in this process results in serious congenital malformations that, if left uncorrected, can lead to blockage of the GI tract, intestinal necrosis and death. There are also broader implications extending to an understanding of cardiac malformations, as looping morphogenesis is not well understood for any tubal organ, and parallels between the primitive gut tube and its dorsal mesentery with early heart tube and its dorsal mesocardium suggest similar biomechanisms may be involved.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD047360-08
Application #
8328923
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Javois, Lorette Claire
Project Start
2004-07-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$325,075
Indirect Cost
$125,875
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Aspiras, Ariel C; Rohner, Nicolas; Martineau, Brian et al. (2015) Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions. Proc Natl Acad Sci U S A 112:9668-73
Shyer, Amy E; Huycke, Tyler R; Lee, ChangHee et al. (2015) Bending gradients: how the intestinal stem cell gets its home. Cell 161:569-80
Kowalko, Johanna E; Rohner, Nicolas; Rompani, Santiago B et al. (2013) Loss of schooling behavior in cavefish through sight-dependent and sight-independent mechanisms. Curr Biol 23:1874-83
Rohner, Nicolas; Jarosz, Dan F; Kowalko, Johanna E et al. (2013) Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. Science 342:1372-5
Kowalko, Johanna E; Rohner, Nicolas; Linden, Tess A et al. (2013) Convergence in feeding posture occurs through different genetic loci in independently evolved cave populations of Astyanax mexicanus. Proc Natl Acad Sci U S A 110:16933-8
Shyer, Amy E; Tallinen, Tuomas; Nerurkar, Nandan L et al. (2013) Villification: how the gut gets its villi. Science 342:212-8
Savin, Thierry; Kurpios, Natasza A; Shyer, Amy E et al. (2011) On the growth and form of the gut. Nature 476:57-62
Saxena, Ankur; Tabin, Clifford J (2010) miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A 107:87-91
Haramati, Sharon; Chapnik, Elik; Sztainberg, Yehezkel et al. (2010) miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 107:13111-6
McGlinn, Edwina; Yekta, Soraya; Mansfield, Jennifer H et al. (2009) In ovo application of antagomiRs indicates a role for miR-196 in patterning the chick axial skeleton through Hox gene regulation. Proc Natl Acad Sci U S A 106:18610-5

Showing the most recent 10 out of 13 publications