Nom1 Mediates Pancreas Development by Regulating Ribosome Biogenesis in Zebrafish

Abstract

Ribosome biogenesis is an important biological process for proper cellular function and development. Defects leading to improper ribosome biogenesis can cause diseases such as Diamond-Blackfan anemia and Shwachman-Bodian-Diamond syndrome. Nucleolar proteins are a large family of proteins and are involved in many cellular processes, including the regulation of ribosome biogenesis. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish line carrying mutation in nucleolar protein with MIF4G domain 1 (nom1), which encodes a conserved nulceolar protein with a role in pre-rRNA processing. Zebrafish nom1 mutants exhibit major defects in endoderm development, especially in exocrine pancreas. Further studies revealed that impaired proliferation of ptf1a-expressing pancreatic progenitor cells mainly contributed to the phenotype. RNA-seq and molecular analysis showed that ribosome biogenesis and pre-mRNA splicing were both affected in the mutant embryos. Several defects of ribosome assembly have been shown to have a p53-dependent mechanism. In the nom1 mutant, loss of p53 did not rescue the pancreatic defect, suggesting a p53-independent role. Further studies indicate that protein phosphatase 1 alpha, an interacting protein to Nom1, could partially rescue the pancreatic defect in nom1 morphants if a human nucleolar localization signal sequence was artificially added. This suggests that targeting Pp1α into the nucleolus by Nom1 is important for pancreatic proliferation. Altogether, our studies revealed a new mechanism involving Nom1 in controlling vertebrate exocrine pancreas formation.

Emerging roles of nucleolar and ribosomal proteins in cancer, development, and aging

“…In zebrafish, mutation in the nucleolar protein NOM1 results in decreased proliferation of pancreatic cells during the development of pancreas. RNA-seq analysis revealed that NOM1 deficiency affects the expression of ribosomal-related genes, leading to the decreased production of 18S rRNA [52]. These data suggest that the regulation of ribosome biogenesis is essential for the proper development of various organs.…”

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

“…Furthermore, ribosomal proteins are often enriched in endodermal organs, and many are required for pancreas development (83). For example, the nucleolar protein Nom1 plays a critical role in ribosomal biogenesis and pancreas development (84). The ribosomal biogenesis factors Bms1 and Wdr43 cause tissue-specific defects in endodermal and neural crest development, respectively (85,86).…”

The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish

“…Impaired development of the pancreas, liver and intestine has been a recurrent pathological feature in many zebrafish models of ribosomopathies, including nil per os ( npo ) [ 60 ], digestive expansion factor ( def ) [ 8 ], titania ( tti ) [ 61 ] and nucleolar protein with MIF4G domain 1 ( nom1 ) [ 62 ]. In contrast, the hematopoietic defects have been studied to a lesser extent; the reported phenotypes are usually limited to primitive erythropoiesis or specification of HSCs as in rpl11 , rps19 , rps7 , rps29 and nop10 mutants [ 16 , 18 , 53 , 63 , 64 ].…”