Organ-Size Regulation in Mammals

Penzo–Méndez, Alfredo; Stanger, Ben Z.

doi:10.1101/cshperspect.a019240

Cited by 74 publications

(87 citation statements)

References 62 publications

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“…In addition, forcing proliferation in fly wing imaginal discs alters cell size, but triggers sufficient apoptosis to maintain organ size (Neufeld et al 1998). We refer the reader to Roth and Walkowiak (2015) and Penzo-Méndez and Stanger (2015) for further discussion of organ size regulation.…”

Section: Introduction: Cells Maintain a Characteristic Cell Sizementioning

confidence: 99%

Cell-Size Control

Amodeo

Skotheim

2015

Cold Spring Harb Perspect Biol

159

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Cells of a given type maintain a characteristic cell size to function efficiently in their ecological or organismal context. They achieve this through the regulation of growth rates or by actively sensing size and coupling this signal to cell division. We focus this review on potential size-sensing mechanisms, including geometric, external cue, and titration mechanisms. Mechanisms that titrate proteins against DNA are of particular interest because they are consistent with the robust correlation of DNA content and cell size. We review the literature, which suggests that titration mechanisms may underlie cell-size sensing in Xenopus embryos, budding yeast, and Escherichia coli, whereas alternative mechanisms may function in fission yeast.

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Section: Introduction: Cells Maintain a Characteristic Cell Sizementioning

confidence: 99%

Cell-Size Control

Amodeo

Skotheim

2015

Cold Spring Harb Perspect Biol

159

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“…This is consistent with the observation that many tissues show both autonomous and regulated growth (109).…”

Section: Introductionsupporting

confidence: 81%

Regulation of Normal and Adaptive Pancreatic Growth

Williams¹

Pancreapedia: Exocrine Pancreas Knowledge Base

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“…The regulation of tissue size is a fundamental question in biology as, in mammals, the adult body mass ranges from ~1.5 grams in the Etruscan shrew to ~1.5 million grams in the blue whale 27 . A direct example of tissue size reduction is observed in the limb size of domesticated animals, such as dogs, cats, and cows, compared to their wild ancestors 19 .…”

Section: Discussionmentioning

confidence: 99%

Minor spliceosome disruption causes limb growth defects without altering patterning

Lemoine

et al. 2020

Preprint

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Disruption of the minor spliceosome causes primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite the importance of minor intron splicing in limb size regulation, its role in limb development remains unexplored. Here we show that loss of U11 small nuclear RNA, an essential minor spliceosome component, results in stunted limbs that maintain patterning. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced due to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. Limb progenitor cells experience delayed prometaphase to metaphase transition and prolonged S-phase, resulting in death of rapidly dividing, distally located progenitors. Consequently, crucial limb patterning genes are upregulated and their expression is maintained spatially to achieve basic patterning. Overall, these findings reveal a potential mechanism shared in disease and domestication.The minor spliceosome, which consists of five small nuclear RNAs (snRNAs) U11, U12, U4atac, U5, and U6atac and associated proteins, splices <0.5% of introns, termed minor introns, found in <2% of genes, termed minor intron-containing genes (MIGs) 1-3 . In metazoans, the minor spliceosome, MIGs, and the position of minor introns within MIGs are all highly conserved 4-6 . This conservation could be explained by the enrichment of MIGs in essential functions required for cell survival 7 , which is consistent with embryonic lethality observed in multiple animal models with constitutive loss of minor spliceosome function [8][9][10] . Consequently, it is unsurprising that human diseases with minor spliceosome loss-of-function mutations have not been discovered. However, mutations that result in partial loss of minor spliceosome function have been reported [11][12][13][14][15][16] .For example, microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), Roifman syndrome (RS), and Lowry-Wood syndrome (LWS) are linked to partial inhibition of the minor spliceosome 11,12,14,16 . Here, individuals harbor disparate mutations in RNU4ATAC, which encodes the U4atac snRNA, and display symptoms including microcephaly, micrognathia, vertebral deficits, and primordial dwarfism 16,17 . The severity of primordial dwarfism observed in MOPD1, RS, and LWS is observed along a gradation, with MOPD1 being the most severe, RS moderate, and LWS mild 16,17 . Nonetheless, in all cases, the basic patterning of the limb skeletal elements, including the presence of a stylopod (humerus; femur), zeugopod (radius/ulna; tibia/fibula), and autopod (hand; foot), is maintained 16,17 .Since unique mutations in RNU4ATAC have been linked to MOPD1, RS, and LWS, the gradation of primordial dwarfism might be due to differential inhibition of the minor spliceosome 16,17 . This suggests that the activity of the minor spliceosome might serve as a rheostat for tissue size cont...

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Organ-Size Regulation in Mammals

Cited by 74 publications

References 62 publications

Cell-Size Control

Cell-Size Control

Regulation of Normal and Adaptive Pancreatic Growth

Minor spliceosome disruption causes limb growth defects without altering patterning

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