Normal Organ Size Research Articles

OR24-4 Homeostatic and Tumourigenic Activity of SOX2+ Pituitary Stem Cells is Controlled by the LATS/YAP/TAZ Cascade

SOX2 positive pituitary stem cells (PSCs) are specified during embryonic development and persist throughout life, giving rise to all anterior pituitary endocrine lineages. We have previously revealed the activation of the LATS/YAP/TAZ signaling cascade in the developing and postnatal mammalian pituitary1, 2. Here, we demonstrate that this pathway functions during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to the expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signaling cascade as an integral component of PSC regulation in normal pituitary physiology and tumourigenesis, of relevance to therapeutic and regenerative medicine approaches. 1. Lodge EJ, et al. Expression Analysis of the Hippo Cascade Indicates a Role in Pituitary Stem Cell Development. Front Physiol. 7, 114 (2016). 2. Xekouki P et al. Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ. Endocr Relat Cancer. (2018).

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade.

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.

The MADS-Box Gene SlMBP21 Regulates Sepal Size Mediated by Ethylene and Auxin in Tomato.

Normal organ size is achieved by successful co-ordination of cell proliferation and cell expansion, which are modulated by multiple factors such as ethylene and auxin. In our work, SlMBP21-RNAi (RNA interference) tomato exhibited longer sepals and improved fruit set. Histological analysis indicated that longer sepals were attributed to cell expansion. To explore how SlMBP21 regulates sepal size, we compared the transcriptomes of sepals between SlMBP21-RNAi and the wild type by RNA sequencing and found that the differentially expressed genes were dominantly related to cell expansion, ethylene and auxin, and photosynthesis. Down-regulation of SlMBP21 affected ethylene production and the free IAA and IAA-Val intensity in sepals. Hormone treatment further indicated that SlMBP21 was involved in the ethylene and auxin pathways. As reported, ethylene and auxin were important factors for cell expansion. Hence, SlMBP21 negatively regulated cell expansion to control sepal size, and ethylene and auxin may mediate this process. Additionally, the contents of Chl and the activity of ribulose-1, 5-bisphosphate carboxylase/oxygenase, the key photosynthetic enzyme, were both increased in SlMBP21-RNAi sepals, which indicated that photosynthesis might be enhanced in transgenic longer sepals. Therefore, the longer sepal, with better protection and enhanced photosynthesis, may contribute to improve fruit set. Altogether, these results suggested that SlMBP21 was a novel factor involved in organ size control. Moreover, our study provided potential application value for improving fruit set.

A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation

We have previously shown the transcription factor SOX9 to be required for the maintenance of multipotential pancreatic progenitor cells in the early embryonic pancreas. However, the association of pancreatic endocrine defects with the Sox9-haploinsufficiency syndrome campomelic dysplasia (CD) implies additional later roles for Sox9 in endocrine development. Using short-term lineage tracing in mice, we demonstrate here that SOX9 marks a pool of multipotential pancreatic progenitors throughout the window of major cell differentiation. During mid-pancreogenesis, both endocrine and exocrine cells simultaneously arise from the SOX9+ epithelial cords. Our analysis of mice with 50%-reduced Sox9 gene dosage in pancreatic progenitors reveals endocrine-specific defects phenocopying CD. By birth, these mice display a specific reduction in endocrine cell mass, while their exocrine compartment and total organ size is normal. The decrease in endocrine cells is caused by reduced generation of endocrine progenitors from the SOX9+ epithelium. Conversely, formation of exocrine progenitors is insensitive to reduced Sox9 gene dosage, thus explaining the normal organ size at birth. Our results show that not only is SOX9 required for the maintenance of early pancreatic progenitors, but also governs their adoption of an endocrine fate. Our findings therefore suggest that defective endocrine specification might underlie the pancreatic phenotype of individuals with CD.

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction. Heart weight; cardiomyocyte size; vascular density normalization; upregulation of hypertrophy markers including atrial natriuretic factor, beta-MHC, and GATA4; and activation of the Akt and MAP kinase pathways were observed at 6 weeks post-induction. Treatment of PR39-induced mice with the eNOS inhibitor L-NAME in the last 3 weeks of a 6-week stimulation period resulted in a significant suppression of heart growth and a reduction in hypertrophic marker expression. Injection of PR39 or another angiogenic growth factor, VEGF-B, into murine hearts during myocardial infarction led to induction of myocardial hypertrophy and restoration of myocardial function. Thus stimulation of vascular growth in normal adult mouse hearts leads to an increase in cardiac mass.

Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1-/- mice, which display a proportional decrease in the sizes of all organs, Akt3-/- mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3-/- but not Akt1-/- mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.

Normal parameters in abdominal radiology of the dog and cat

ABSTRACTThe size, position and ease of demonstration of the major abdominal viscera have been recorded in a series of two hundred consecutive radiographic examinations of the dog and cat. Only the values for viscera either known to be normal following surgery or autopsy, or presumed to be normal on the basis of clinical findings, are presented. All values are expressed as a ratio of the length of the second lumbar vertebral body. The factors affecting organ visibility and the variations in normal organ size are discussed.