The molecular basis of lung morphogenesis

XBP-1 is a CREB/ATF family transcription factor highly expressed in hepatocellular carcinomas. Here we report that XBP-1 is essential for liver growth. Mice lacking XBP-1 displayed hypoplastic fetal livers, whose reduced hematopoiesis resulted in death from anemia. Nevertheless, XBP-1-deficient hematopoietic progenitors had no cell-autonomous defect in differentiation. Rather, hepatocyte development itself was severely impaired by two measures: diminished growth rate and prominent apoptosis. Specific target genes of XBP-1 in the liver were identified as aFP, which may be a regulator of hepatocyte growth, and three acute phase protein family members. Therefore, XBP-1 is a transcription factor essential for hepatocyte growth.

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An essential role in liver development for transcription factor XBP-1

The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), beta-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.

https://www.physiology.org/doi/pdf/10.1152/physrev.00028.2006

Transcriptional Control of Lung Morphogenesis

The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.

p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway

The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

Mandavi Singh

Papers

Mouse ATF-2 Null Mutants Display Features of a Severe Type of Meconium Aspiration Syndrome