Melanocyte homeostasis in vivo tolerates <i>Rb1</i> loss in a developmentally independent fashion

Tonks, Ian D.; Mould, Arne W.; Schroder, Wayne A.; Hacker, Elke; Bosenberg, Marcus W.; Hayward, Nicholas K.; Walker, Graeme J.; Kay, Graham F.

doi:10.1111/j.1755-148x.2010.00722.x

Cited by 2 publications

(1 citation statement)

References 24 publications

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“…To determine the cause of death, Rb1 cKO animals were subjected to necropsy for gross and histopathologic examination of all major organs. We did not observe any melanocyte defects or tumors, similar to results of Tonks et al (21), but early death prevented the study of late-onset melanoma. The only abnormality detected was marked dilation of the distal small intestine (DSI) with intraluminal stool or air accumulation and contraction of the more distal bowel.…”

Section: Rb1 Loss In the Ens Causes A Severe Intestinal Motility Disosupporting

confidence: 90%

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Fu¹,

Landreville

Agapova

et al. 2013

J. Clin. Invest.

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The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest-derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre + ;Rb1 fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS. IntroductionChronic intestinal pseudo-obstruction (CIPO) is the clinical indication for 9 percent of small bowel transplants (1), yet the etiology for these disorders remains poorly understood. CIPO is diagnosed when bowel motility defects cause functional, but not mechanical, obstruction, leading to abdominal distension, pain, malnutrition, and, in severe cases, dependence on parenteral nutrition or intestinal transplantation for survival. It is likely that diverse genetic, infectious, autoimmune, metabolic, and toxic insults all contribute to CIPO etiology.Intestinal motility and many other aspects of bowel function are controlled by an interconnected intrinsic network of neurons and glia called the enteric nervous system (ENS) (2-4). The ENS forms from neural crest-derived cells that migrate through fetal bowel, proliferate extensively, and then exit the cell cycle and differentiate into many different neuronal subtypes (5-7). Defects in specific types of enteric neurons may cause life-threatening disease, and, like in the central nervous system, neurons in the ENS must be present in the proper ratios and with correct patterning for the bowel to work well. Signals that control ENS precursor proliferation and cell cycle exit are incompletely understood. Furthermore, the ENS can be damaged in many ways, often with preferential effects on NO-producing enteric neurons that inhibit bowel contraction (8). There are also regional differences in the susceptibility of enteric neurons to damage that are not well understood (9).We initially intended to develop a model of melanoma by deleting the tumor suppressor retinoblastoma 1 (Rb1) in melanocytes,

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Section: Rb1 Loss In the Ens Causes A Severe Intestinal Motility Disosupporting

confidence: 90%

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Fu¹,

Landreville

Agapova

et al. 2013

J. Clin. Invest.

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Melanocyte transformation requires complete loss of all pocket protein function via a mechanism that mitigates the need for MAPK pathway activation

et al. 2017

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Deregulation of p16INK4A is a critical event in melanoma susceptibility and progression. It is generally assumed that the major effect of loss of p16 function is mediated through the CDK-cyclin pathway via its influence on the pocket protein (PP) pRb. However, there are also two other PPs, p107 and p130, which, when phosphorylated by CDK-cyclin complexes, play a role in permitting cell progression. Cohorts of mice carrying melanocyte-specific knockouts (KOs) of various combinations of the three PPs were generated. Mice null for pRb, p107, p130 or any combination of double mutants did not develop melanoma. Surprisingly, melanocyte-specific loss of all three PPs facilitated melanoma development (median age of onset 308 days, penetrance 40% at 1 year). Tumorigenesis was exacerbated by Trp53 co-deletion (median age of onset 275 days, penetrance 82% at 1 year), with cell culture studies indicating that this difference may result from the apoptotic role of Trp53. Melanomas in PP;Trp53-deficient mice lacked either Ras or Braf mutations, and hence developed in the absence of constitutive MAPK pathway activation. The lag period between induction of total PP or PP/Trp53 KO and melanoma development indicates that additional genetic or epigenetic alterations may account for neoplastic progression. However, exome sequencing of PP;Trp53 KO melanomas failed to reveal any additional recurrent driver mutations. Analysis of the putative mutation signature of the PP;Trp53 KO melanomas suggests that melanocytes are primed for transformation via a mutagenic mechanism involving an excess of T>G substitutions, but not involving a preponderance of C>T substitutions at CpG sites, which is the case for most spontaneous cancers not driven by a specific carcinogen. In sum, deregulation of all three PPs appears central to neoplastic progression for melanoma, and the customary reference to the p16/CDK4/pRB pathway may no longer be accurate; all PPs are potentially critical targets of CDK-cyclins in melanoma.

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Melanocyte homeostasis in vivo tolerates Rb1 loss in a developmentally independent fashion

Cited by 2 publications

References 24 publications

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Melanocyte transformation requires complete loss of all pocket protein function via a mechanism that mitigates the need for MAPK pathway activation

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