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Lori  Sussel
Lori Sussel
Associate Professor of Genetics and Development in the Naomi Berrie Diabetes Center


Address: 1150 St. Nicholas Avenue Russ Berrie Pavillion Rm 607-B New York NY 10032
Phone: 212-851-5115
Fax: 212-851-5236
E-mail:

lgs2@columbia.edu

Education and Training:
Ph.D. 1993, Columbia University
Postdoctoral Fellowship 1993-1994, UC Berkeley
Postdoctoral Fellowship 1994-1998, UC San Francisco
Affiliations:
bullet  Genetics and Development
bullet  Naomi Berrie Diabetes Center
bullet  Columbia Stem Cell Initiative
bullet  Integrated Graduate Program in Cellular, Molecular and Biomedical Studies
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Training Activities:
bullet  Genetics and Development
bullet  Integrated Graduate Program in Cellular, Molecular and Biomedical Studies
Research Summary:
(800 words, max)
Transcriptional regulation of cell specification in the mouse. We are primarily focused on the differentiation, development and function pancreatic islets cells and the specification of neuronal populations in the hindbrain and spinal cord.
Current Research:
Overview

The main focus of the Sussel laboratory is to understand the complex transcriptional networks that regulate development, differentiation and function of the pancreas. The pancreas is comprised of two major functional compartments derived from a common progenitor pool: the exocrine pancreas produces enzymes for digestion and the endocrine pancreas is required to maintain energy homeostasis. The endocrine pancreas is further organized into clusters of cells called the islets of Langerhans, which are comprised of four well-defined hormone-producing cell types: alpha (α), beta (β) cells, delta (δ) and pancreatic polypeptide (PP) cells. Our lab also identified a fifth cell type in the developing islet, the epsilon (ε) cell that produces the hormone ghrelin. The β cells represent the largest population of islet cells and produce insulin, a hormone critical for life. While all the cells of the endocrine pancreas are thought to arise from a common precursor, the early process of lineage determination and cell-type differentiation within the pancreas is unclear. To date, only a handful of regulatory factors involved in pancreas development have been identified and many of the molecular pathways that specify islet cell differentiation are poorly understood. For this reason, we are using molecular biology and mouse genetics to identify the coding and non-coding genes that are involved in the development of the pancreas and in the regulation of islet cell differentiation and function. In particular, we are exploring the following areas of research:

Pancreas induction during embryonic development

The Gata family of zinc finger transcription factors is important in many developmental processes. We have determined that Gata4 and Gata6 have dynamic expression patterns during embryonic development and that Gata6 plays essential roles during pancreas formation and subsequent endocrine cell development. We are currently studying conditional (floxed) alleles of Gata4 and Gata6 to determine their precise functions during islet development. These studies have led to the important discovery that Gata4 and Gata6 are not required for the initial specification of the pancreas domain within the developing foregut endoderm, but function redundantly to control the outgrowth and differentiation of the pancreas. Simultaneous disruption of both Gata4 and Gata6 lead to pancreatic agenesis by birth. Genetic and molecular studies are ongoing to determine the common and distinct pathways regulated by the Gata factors in the pancreas, liver and heart.

Pancreatic islet cell fate specification

During pancreas development, the specification of individual islet cell fates from a common Neurogenin3+ endocrine progenitor cell is an essential step in the generation of insulin-producing beta cells. We have determined that Nkx2.2, an essential homeodomain containing transcription factor plays a key role in islet cell fate decisions. Null mutations in Nkx2.2 result in the production of excess ghrelin cells at the expense of all beta cells and the majority of alpha and PP cells. Understanding how these important cell fate decisions are regulated will be crucial for the successful generation of functional beta cells from alternative sources, including stem cell populations. We have used Recombination Mediated Cassette Exchange (RMCE) technology to generate mutant alleles of Nkx2.2 and we have generated a conditional allele of Nkx2.2. These novel tools will allow us to determine the precise temporal and spatial functions of Nkx2.2 during pancreas development. These studies have already implicated DNA methylation as a major factor in the specification and maintenance of islet cell fates in the embryo and in the adult. We are also exploring the complex transcriptional regulatory networks that function upstream, downstream and in parallel with Nkx2.2 to specify and maintain each islet cell fate.

Beta cell maturation and function

A very poorly understood process in the in vitro and in vivo generation of beta cells is the transition to a fully glucose-responsive functionally mature cell. In the mouse, the maturation step is executed in the first few weeks of life, likely in response to environmental signals. We have determined that NeuroD1 is an important regulator of the beta cell maturation process. We are using mouse genetics, molecular biology and high-throughput sequencing analysis to explore the upstream and downstream regulatory events necessary for the initiation and maintenance of fully functional beta cells in vitro and in vivo.

The role of non-coding RNAs and epigenetic modifications in regulating islet development and functions

Although we have identified many of the transcriptional regulators that are necessary for islet cell development and function, there are many aspects of the regulatory process that remain a mystery and/or cannot be resolved with our current molecular tools. We have embarked on the analysis of long non-coding (lnc) RNAs that might function in the known transcription factor network pathways. These studies have identified several lncRNAs that are regulated by Neurogenin3 and/or Nkx2.2 and potentially regulate the development, differentiation or function of beta cells. In addition, we have identified an important role for DNA methylation in mediating the transcriptional events that regulate islet cell identity. These studies will clarify the complex inter-relationships between DNA modifications, coding genes and non-coding genes to regulate important developmental decisions and cell lineage choices.
Regulation of cell fate decisions in the intestine and CNS
Our discovery of Nkx2.2 in the regulation of cell fate decisions in the pancreas have led us to explore other tissues where Nkx2.2 is expressed in progenitor populations: the intestine and CNS. We are using our novel mouse genetics tools to study the function of Nkx2.2 regulating enteroendocrine cell fate decisions in the intestine. Furthermore, we are defining the role of Nkx2.2 in specifying ventral neuron cell fates in the spinal cord and hindbrain. These studies are clarifying how common sets of transcriptional factors can regulate distinct molecular pathways to define cell fate decisions in diverse sets of tissues.
Publications:
(6 max)
1. Mastracci, T.L., Anderson, K.R., and Sussel, L: (2013) Regulation of Neurod1 contributes to the lineage potential of Neurogenin3+ endocrine precursor cells.  PLoS Genetics  Feb;9(2): e1003278

2. Talchai C, Xuan S, Lin HV, Sussel, L., Accili D: (2012) Pancreatic beta cell dedifferentiation as mechanisms of diabetic beta cell failure.  Cell  150: 1223-12234

3. Xuan S, Borok MJ, Decker KJ, Battle MA, Duncan SA, Hale MA, Macdonald RJ, Sussel L: (2012) Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis.  J Clin Invest  122: 3516-3528

4. Papizan, J.B., Singer, R.A., Tschen, S., Dhawan, S., Schrunk, J.M., Hipkens,S.B., Magnuson, M.A., Bhushan, A. and Sussel, L: (2011) Nkx2.2 preferentially recruits a repressor complex to the methylated Arx promoter to maintain beta cell identity.  Genes and Development  5: 2291-2305

5. Anderson, K.R., Balderes, D.A., Singer, R.A., Johnson, C.W., Artinger, K.B. and Sussel, L: (2011) The L6 domain tetraspanin, Tm4sf4, regulates endocrine pancreas differentiation and directed cell migration..  Development  138: 3213-3224

6. Gu, C.Y., Stein, G., Goebbels, S., Hörnberg, H., Nave, K., Herrera, P., White, P., Kaestner, K.H., Sussel, L. and Lee, J.E: (2010) Pancreatic beta cells require NeuroD to achieve and maintain functional maturity.  Cell Metabolism  11: 298-310

URL for lab page:
 http://sussellab.org/

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