Research in the Sussel lab combines molecular biology techniques and mouse embryology to study the role of regulatory factors in specifying the development and differentiation of the pancreas during mouse embryogenesis. The pancreas is an essential organ required to maintain energy balance in the body; disruption of pancreatic function leads to Diabetes. The endocrine pancreas is organized into clusters of cells called the islets of Langerhans, which are comprised of four well-defined hormone-producing cell types: alpha (?), beta (?), delta (?) and PP cells. In addition, our lab has recently discovered the presence of a fifth cell type in the islet, which produces the hormone ghrelin. The ? 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 the molecular pathways that specify islet cell differentiation are poorly understood. For this reason, we are attempting to identify the regulatory genes that are involved in the development of pancreatic islet precursors, islet cell development and differentiation, and the propagation of ? cells or their precursors. Projects in the lab are specifically focused on understanding the molecular mechanisms that determine how the pancreas initially develops in the mouse embryo and how the different islet cell populations are specified. In particular, we have demonstrated that homeobox transcription factor, Nkx2.2 is essential for the specification of most glucagon-producing ? cells and all insulin-producing ? cells in the islet. We have generated an Nkx2.2 knockout mouse model that disrupts Nkx2.2 function. These mice fail to differentiate their ? cells, produce no insulin, and die of diabetes shortly after birth. Surprisingly, these mice were found to have islets filled with ghrelin-producing cells, which appear to replace the ? cell population. Studies in the lab are focused on determining the molecular mechanisms by which Nkx2.2 functions in the endocrine pancreas to regulate these early islet cell fate decisions. Recently, we have used in vivo genetic approaches to determine that Nkx2.2 functions primarily as a transcriptional repressor to specify the ? cell fate and the immature ? cell population. We are currently using several biochemical and molecular techniques to identify Nkx2.2 interacting partners and its downstream targets in the pancreas. We are also performing structure-function analysis of the Nkx2.2 gene, in vitro and in vivo.

Publications

PubMedID	Citation
16887115	Decker K, Goldman DC, Grasch CL, Sussel L. Gata6 is an important regulator of mouse pancreas development. (2006) Dev Biol 298: 415-29
16847327	Raum JC, Gerrish K, Artner I, Henderson E, Guo M, Sussel L, Schisler JC, Newgard CB, Stein R. FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site. (2006) Mol Cell Biol 26: 5735-43
16339193	Prakash N, Brodski C, Naserke T, Puelles E, Gogoi R, Hall A, Panhuysen M, Echevarria D, Sussel L, Weisenhorn DM, Martinez S, Arenas E, Simeone A, Wurst W. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. (2006) Development 133: 89-98
15053900	Doyle MJ, Sussel L. Engineering islets: lessons from stem cells and embryonic development. (2004) Endocrinol Metab Clin North Am 33: 149-62, x
14970313	Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. (2004) Proc Natl Acad Sci U S A 101: 2924-9
14729487	Wang J, Elghazi L, Parker SE, Kizilocak H, Asano M, Sussel L, Sosa-Pineda B. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. (2004) Dev Biol 266: 178-89
12426319	Cissell MA, Zhao L, Sussel L, Henderson E, Stein R. Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2. (2003) J Biol Chem 278: 751-6
11526078	Qi Y, Cai J, Wu Y, Wu R, Lee J, Fu H, Rao M, Sussel L, Rubenstein J, Qiu M. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain (2001) Development 128: 2723-33
11076772	Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. (2000) Development 127: 5533-40
10903178	Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD, German MS. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. (2000) Development 127: 3533-42
10393115	Sussel L, Marin O, Kimura S, Rubenstein JL. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal (1999) Development 126: 3359-70
10217145	Briscoe J, Sussel L, Serup P, Hartigan-O'Connor D, Jessell TM, Rubenstein JL, Ericson J. Homeobox gene Nkx2.2 and specification of neuronal identity by graded (1999) Nature 398: 622-7
9584121	Sussel L, Kalamaras J, Hartigan-O'Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due (1998) Development 125: 2213-21
9533954	Qiu M, Shimamura K, Sussel L, Chen S, Rubenstein JL. Control of anteroposterior and dorsoventral domains of Nkx-6.1 gene (1998) Mech Dev 72: 77-88