Dataset Information

TGF-? Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (Petromyzon marinus).

ABSTRACT: Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (Petromyzon marinus), in which BA occurs naturally during metamorphosis. With the likelihood of conserved developmental mechanisms underlying organogenesis and degeneration, lamprey developmental BA may be a useful model to infer mechanisms underlying human embryonic BA. We reasoned that hepatobiliary transcriptomes regulate the transition between landmark stages of BA. Therefore, we examined sea lamprey hepatobiliary transcriptomes at four stages (M0, metamorphic stage 0 or larval stage, no BA; M2, metamorphic stage 2, onset of BA; M5, metamorphic stage 5, BA, and heightened hepatocyte proliferation and reorganization; and JV, juvenile, completion of BA) using messenger RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We found gene-expression patterns associated with the transition between these stages. In particular, transforming growth factor ? (TGF-?), hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Wnt, and mitogen-activated protein kinase pathways were involved during biliary degeneration. Furthermore, disrupting the TGF-? signaling pathway with antagonist or small interfering RNA treatments at the onset of BA delayed gall bladder and bile duct degeneration. Conclusion: Distinctive gene-expression patterns are associated with the degeneration of the biliary system during developmental BA. In addition, disrupting TGF-? signaling pathway at the onset of BA delayed biliary degeneration.

SUBMITTER: Chung-Davidson YW

PROVIDER: S-EPMC6996360 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TGF-β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (<i>Petromyzon marinus</i>).

Chung-Davidson Yu-Wen YW Ren Jianfeng J Yeh Chu-Yin CY Bussy Ugo U Huerta Belinda B Davidson Peter Joseph PJ Whyard Steven S Li Weiming W

Hepatology communications 20191224 2

Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (<i>Petromyzon marinus</i>), in which BA occurs naturally during metamorphosis. With the like ...[more]

PMID: 32025607

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Project description:The sea lamprey, Petromyzon marinus, is an anadromous, semelparous species that is vulnerable to endangered in parts of its native range due in part to loss of spawning habitat because of man-made barriers. The ability of lampreys to return to the ocean or estuary and search out alternative spawning river systems would be limited by their osmoregulatory ability in seawater. A reduction in tolerance to salinity has been documented in migrants, although the underlying mechanisms have not been characterized. We examined the capacity for marine osmoregulation in upstream spawning migrants by characterizing the physiological effects of salinity challenge from a molecular perspective. Estuarine-captured migrants held in freshwater (FW) for ∼1 week (short-term acclimation) or 2 months (long-term acclimation) underwent an incremental salinity challenge until loss of equilibrium occurred and upper thresholds of 25 and 17.5, respectively, occurred. Regardless of salinity tolerance, all lamprey downregulated FW ion-uptake mechanisms [gill transcripts of Na(+):Cl(-) cotransporter (NCC/slc12a3) and epithelial Na(+) channel (ENaC/scnn1) and kidney Na(+)/K(+)-ATPase (NKA) protein and activity but not transcript]. At their respective salinity limits, lamprey displayed a clear osmoregulatory failure and were unable to regulate [Na(+)] and [Cl(-)] in plasma and intestinal fluid within physiological limits, becoming osmocompromised. A >90% drop in haematocrit indicated haemolysis, and higher plasma concentrations of the cytosolic enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase indicated damage to other tissues, including liver. However, >80% of short-term FW-acclimated fish were able to osmoregulate efficiently, with less haemolysis and tissue damage. This osmoregulatory ability was correlated with significant upregulation of the secretory form of Na(+):K(+):2Cl(-) cotransporter (NKCC1/slc12a2) transcript levels and the re-emergence of seawater-type ionocytes detected through immunohistochemical NKA immunoreactivity in the gill, the central ionoregulatory organ. This work sheds light on the molecular and physiological limits to the potential return to seawater for lampreys searching for alternative FW systems in which to spawn.

Dataset Information

TGF-? Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (Petromyzon marinus).

Publications

TGF-β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (<i>Petromyzon marinus</i>).

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