Post-transcriptional control of development and disease

 

 Neural crest (NC) cells are an essential, multipotent cell population in the vertebrate embryo. During development, these cells must undergo coordinated induction, specification, and epithelial—mesenchymal transition (EMT) events to migrate and ultimately develop into a wide range of cell types (e.g. craniofacial cartilage/bone, peripheral neurons/glia). The transcriptional control of these cell state transitions has been dissected and mapped into feed-forward gene regulatory networks (GRNs), which help explain the detailed sequence of events involved in NC development.

Recently however, I have found there is a significant, heretofore underappreciated role for RNA-binding protein (RBP)- and RNA granule-mediated post-transcriptional regulation in modulating the output of these GRNs and, subsequently, NC cell fate decisions. 

My lab will seek to map the post-transcriptional regulatory logic and intrinsic cellular mechanisms underlying NC GRN output and, subsequently, developmental fate decisions. We will leverage systems-level approaches and cutting-edge developmental biology techniques to understand how NC cell state transitions are achieved post-transcriptionally to drive cell fate choices. By uncovering how NC cells modulate GRN output to direct cell fate decisions, my goal is to gain insights into how these programs fail during development or may be hijacked during disease towards future therapeutic applications.

 Postdoctoral Research Accomplishments

NC GRNs control cell state transitions such as EMT, where premigratory NC (pNC) cells undergo a coordinated exit from the neural tube (NT) to become migratory (mNC). I discovered that Draxin extrinsically modulates the EMT GRN (Œ1), and is itself controlled intrinsically through post-transcriptional regulation (2).

1. Extrinsic modulation of NC cell state transitions via Draxin-mediated attenuation of Wnt signaling: 

To understand how NC EMT is controlled, I analyzed stage-specific NC transcriptomes to identify genes differentially expressed between the premigratory and migratory stages. Draxin, which encodes a secreted canonical Wnt antagonist, is expressed in a transient head-to-tail wave within premigratory NC and is rapidly downregulated at the onset of EMT. In parsing the cellular mechanism, I found that Draxin functions extracellularly to suppress canonical Wnt signaling, and it is the timing of Draxin expression that controls the maintenance of the specification GRN and activation of the EMT GRN (Hutchins and Bronner, 2018; Hutchins and Bronner, 2019), illustrating a novel and important cell biological mechanism for the temporal control of NC GRNs.

2. Intrinsic modulation of NC cell state transitions through post-transcriptional regulation:

As described above, I discovered that NC cell state transitions, particularly EMT, are controlled by the transient expression of Draxin, which must be rapidly downregulated. To identify how Draxin expression is regulated, I adapted in vivo reporters and a live RNA imaging approach and found that Draxin mRNA localized to processing bodies (P-bodies) for decay. P-bodies are cytoplasmic granules involved in RNA turnover and storage. P-body disruption abrogated Draxin mRNA degradation, and subsequently caused defects in NC migration (Hutchins et al., 2020). This work provides the first evidence that full and rapid mRNA decay of a molecular rheostat controls NC cell state transition. To parse the mechanisms underlying the transition of Draxin mRNA stability to decay, I applied in silico approaches and identified an RBP, Elavl1/HuR, that targets Draxin mRNA; indeed, I observed that downregulation of Elavl1 destabilized Draxin mRNA and altered NC cell fate decisions (Hutchins et al., 2022). Taken together, my postdoctoral work establishes critical roles for RBPs and RNA granules in the post-transcriptional modulation of NC GRN output.

 Ongoing and Planned Research

  1. Identification of post-transcriptional regulatory linkages controlling early NC fate decisions

  2. Parsing the intersection of intrinsic and extrinsic factors with post-transcriptional regulation

  3. Leveraging post-transcriptional regulatory linkages controlling EMT and migration in NC and NC-derived cancer

 

Let’s Work Together

The lab is recruiting enthusiastic graduate students and postdocs interested in applying single-molecule and live imaging studies, and quantitative cell and developmental biology techniques in pursuit of a deeper understanding of cell fate choices.

Please contact me regarding positions. Graduate students must first be accepted into the DSCB, BMS, or OCS graduate program at UCSF.