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Keeping your organs in shape: Transcriptional and cellular control of tissue morphogenesis.

Organ shape acquisition requires intricate coordination of the morphogenetic repertoire during which tissues are bent, pulled, and moved. One striking example is the formation of the digestive system where complex looping and bending events shape the gut tube as it elongates. Our laboratory takes advantage of the chicken embryo as a classical embryological model to understand the molecular and cellular events that direct the formation of tissues and organs during vertebrate embryogenesis. Specifically, we seek to learn how information received from cell signaling is integrated to ultimately determine distinct cellular behaviors and cell shape during development.

We previously showed that directional gut looping is initiated by left-right asymmetries in the architecture of the dorsal mesentery downstream of the early Nodal/Pitx2 left-right symmetry-breaking cascade. Specifically, the dorsal mesentery of embryonic gut consists of strikingly asymmetric cellular morphologies leading to its mechanical deformation and a resulting leftward tilt of the primitive gut tube. This asymmetric architecture includes condensation of mesenchymal cells specifically on the left side. Moreover, the overlying epithelium on the left exhibits columnar cell morphology, in contrast to the cuboidal morphology on the right side of the dorsal mesentery. Importantly, the generation of this initial tilt is critical to subsequent morphogenesis of the gut as it provides a left-right bias for the specification of the direction of intestinal coiling. Our data demonstrate that discrete transcriptional events drive morphological changes in cell shape and cell behavior that impart mechanical force within the dorsal mesentery, tilting the gut tube to the left.

Combining the versatility of the classical chicken embryo with the strength of functional genomics our laboratory uses the dorsal mesentery as a model to describe the genetic program driving tissue morphogenesis, particularly cell shape. Using Laser Capture Microdissection, we first separate the mesentery into four morphologically and functionally distinct compartments (Left Epithelia, Left Mesenchyme, Right Mesenchyme, and Right Epithelia) at a developmental time when the dorsal mesentery becomes strikingly asymmetric and when the initial leftward tilt of the midgut is first observed. We then collect the RNA from each of the four mesenteric compartments and analyze it using the GeneChip chicken genome array (Affymetrix).

Our laboratory is also interested in understanding mammary gland morphogenesis. The mouse mammary gland is an extraordinary experimental tool to study numerous aspects of tissue morphogenesis. The mammary gland is easily accessible to surgical manipulations and most of its development occurs postnatally providing further access to the tissue during development. Mammary epithelial stem cells self-renew with each cycle of pregnancy and provide the opportunity to serially transplant fragments of the mammary gland over time.

We recently showed that the Pea3 Ets transcription factor is expressed in the progenitor cells of the embryonic and adult mouse mammary gland and that loss of this gene resulted in an aberrant morphogenesis of this organ. During pregnancy, mammary glands isolated from Pea3-null females have impaired alveolar development as revealed by a decreased fraction of alveolar structures important to milk production. In addition, colony forming assays of mammary epithelial cells reveal that loss of Pea3 alters the distribution of specific multipotent progenitor cells.

To understand the functional mechanism of Pea3 our laboratory takes advantage of mouse genetics and the mammary transplantation assay to determine the downstream cellular effectors of Pea3 signaling during mammary gland development.