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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, ?-CATENIN, and ?-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.

SUBMITTER: Moran TB

PROVIDER: S-EPMC3033053 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation.

Moran Tyler B TB Goldberg Leah B LB Serviss Sarah L SL Raetzman Lori T LT

Molecular endocrinology (Baltimore, Md.) 20101117 1

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, bu ...[more]

PMID: 21084383

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Project description:Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls. The hippocampus (pes and body), parahippocampal gyrus, amygdala, temporal pole and temporal cortex were examined with DCX immunohistochemistry using four commercially-available DCX antibodies, labelled cells were quantified in different regions of interest as well as their co-expression with cell type specific markers (CD68, Iba1, GFAP, GFAP?, nestin, SOX2, CD34, OLIG2, PDGFR?, NeuN) and cell cycle marker (MCM2). Histological findings were compared with clinical data, as well as gene expression data obtained from the temporal cortex of 83 temporal lobe epilepsy cases with HS. DCX immunohistochemistry identified immature (Nestin-/NeuN-) neurons in layer II of the temporal neocortex in patients with and without epilepsy. Their number declined significantly with age but was not associated with the presence of hippocampal sclerosis, seizure semiology or memory dysfunction. DCX+ cells were prominent in the paralaminar nuclei and periamygdalar cortex and these declined with age but were not significantly associated with epilepsy history. DCX expressing cells with ramified processes were prominent in all regions, particularly in the hippocampal subgranular zone, where significantly increased numbers were observed in epilepsy samples compared to controls. DCX ramified cells co-expressed Iba1, CD68 and PDGFR?, and less frequently MCM2, OLIG2 and SOX2, but no co-localization was observed with CD34, nestin or GFAP/GFAP ?. Gene expression data from neocortical samples in patients with TLE and HS supported ongoing DCX expression in adults. We conclude that DCX identifies a range of morphological cell types in temporal lobe epilepsy, including immature populations, glial and microglial cell types. Their clinical relevance and biological function requires further study but we show some evidence for alteration with age and in epilepsy.

Dataset Information

Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation.

Publications

Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation.

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