Scott T. Dougan

My laboratory studies the molecular and cellular basis of pattern formation in vertebrate embryos.  In all multicellular organisms, cells differentiate according to their relative position in the embryo, generating a highly reproducible pattern of cell fates.  The body plan is established at early stages by specialized groups of cells, called signaling centers. These tissues act by emitting signals that instruct the fates of neighboring cells. The long-term goal of my research is to understand how signaling centers function.  In particular, my laboratory focuses on three questions: (1) How are signaling centers established and maintained?; (2) How do surrounding cells interpret signals from these tissues?; and (3) How do signaling centers transmit positional information asymmetrically to surrounding cells?  We address these questions using the powerful vertebrate genetic model system, the zebrafish.

Patterning the germ layers

Nodal-related proteins are a subclass of the TGF-beta superfamily which are required in all vertebrates to induce the mesoderm and endoderm, pattern all three germ layers, and establish the left-right body axis. The prevailing view is that these proteins act as morphogens, forming a concentration gradient within the surrounding tissue and specifying cell fates in a dosage dependent manner.  In contrast, our results indicate that cells respond to the total cumulative dose to which they are exposed, as a function of their distance from the source of Nodal signals and the duration of their exposure.  We are currently exploring the molecular mechanism by which cells record how long they are exposed to Nodal signals.

Signaling from extra-embryonic tissues

In zebrafish, the extra-embryonic yolk syncytial layer (YSL) is a dynamic source of patterning signals.  At early stages, Nodal signals produced in the YSL induce the endoderm and head mesoderm.  During gastrulation, BMP signals from the YSL induce the ventral tailfin.  We have discovered that an atypical T-box containing transcription factor homologous to the mammalian Max-gene associated (Mga) protein is at the center of a complex regulatory network in the YSL.  Zebrafish Mga is a large (~2700 amino acids) protein, with a T-box domain located at the N-terminus and a basic helix-loop-helix domain at the C-terminus.  We are currently elucidating the mechanisms by which this protein controls expression of both the BMP and Nodal-related proteins in the YSL, and also controls the activity of the MYC transcription factor.

Asymmetric, cilia-dependent signaling

There is growing evidence that the establishment of left-right asymmetry in the embryo requires a unidirectional beating action of cilia within the transient Kupffer¹s vesicle, and similar tissues in other vertebrates. Axonemes of cilia are inherently asymmetric, microtubule-based structures that are found on nearly every non-dividing vertebrate cell.  The internal chirality of cilia determines the directionality of the ciliary beat, which in turn determines the directionality of fluid flow.  Ciliary microtubules acquire a wide variety of post-translational modifications (PTMs), including the addition of polyglycine and polyglutamate to the C-termini of alpha and beta-tubulin, which are distributed asymmetrically throughout the axoneme.  In a collaborative project with the Gaertig lab, our goal is to understand how structural asymmetry is established within the cilia, and how this translates into directional motility essential for embryonic development in zebrafish.