title: Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation.
abstract: The pituitary gland contains six distinct hormone-secreting cell types that are essential for basic physiological processes including fertility and responding to stress. Formation of hormone-secreting cells during development relies on Notch signaling to prevent progenitors from prematurely differentiating. The nature of the signal curtailing Notch signaling in the pituitary is unknown, but a good candidate is the endocytic adaptor protein NUMB. NUMB targets Notch for proteolytic degradation, but it also has a broad range of actions, including stabilizing adherens junctions through interactions with cadherins and influencing cell proliferation by stabilizing expression of the tumor suppressor protein p53. Here, we show that NUMB and its closely related homolog, NUMBLIKE, are expressed in undifferentiated cells during development and later in gonadotropes in the anterior lobe and melanotropes of the intermediate lobe. All four isoforms of NUMB, are detectable in the pituitary, with the shorter forms becoming more prominent after adolescence. Conditionally deleting Numb and Numblike in the intermediate lobe melanotropes with Pomc Cre mice dramatically alters the morphology of cells in the intermediate lobe, coincident with impaired localization of adherens junctions proteins including E-CADHERIN, N-CADHERIN, β-CATENIN, and α-CATENIN. Strikingly, the border between posterior and intermediate lobes is also disrupted. These mice also have disorganized progenitor cells, marked by SOX2, but proliferation is unaffected. Unexpectedly, Notch activity appears normal in conditional knockout mice. Thus, Numb is critical for maintaining cell-cell interactions in the pituitary intermediate lobe that are essential for proper cell placement.
authors.affiliation: University of Illinois at Urbana-Champaign, 407 South Goodwin Avenue, Urbana, Illinois 61801, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Moran
authors.forename: Leah B
authors.initials: LB
authors.lastname: Goldberg
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Serviss
authors.forename: Lori T
authors.initials: LT
authors.lastname: Raetzman
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D052681:Gonadotrophs / Q000166:cytology / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D052717:Melanotrophs / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D052716:Pituitary Gland, Intermediate / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; C106292:Numbl protein, mouse; D020033:Protein Isoforms; D051880:Receptors, Notch; D011333:Pro-Opiomelanocortin; C045073:Cre recombinase; D019426:Integrases