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An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors.

ABSTRACT: Appropriate development of nervous system connectivity involves a variety of processes, including neuronal life-and-death decisions, differentiation, axon guidance and migration, and synaptogenesis. Although these activities likely require specialized signaling events, few substrates unique to these neurotrophic functions have been identified. Here we describe the cloning of ankyrin repeat-rich membrane spanning (ARMS), which encodes a novel downstream target of neurotrophin and ephrin receptor tyrosine kinases, Trk and Eph, respectively. The amino acid sequence of ARMS is highly conserved from nematode to human, suggesting an evolutionarily conserved role for this protein. The ARMS protein consists of 1715 amino acids containing four putative transmembrane domains, multiple ankyrin repeats, a sterile alpha motif domain, and a potential PDZ-binding motif. In the rat, ARMS is specifically expressed in the developing nervous system and in highly plastic areas of the adult brain, regions enriched in Trks and Eph receptors. ARMS can physically associate with TrkA and p75 neurotrophin receptors. Moreover, endogenous ARMS protein is tyrosine phosphorylated after neurotrophin treatment of pheochromocytoma 12 cells and primary hippocampal neurons or ephrin B treatment of NG108-15 cells, demonstrating that ARMS is a downstream target for both neurotrophin and ephrin receptors.

SUBMITTER: Kong H

PROVIDER: S-EPMC6762419 | biostudies-literature | 2001 Jan

REPOSITORIES: biostudies-literature

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An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors.

Kong H H Boulter J J Weber J L JL Lai C C Chao M V MV

The Journal of neuroscience : the official journal of the Society for Neuroscience 20010101 1

Appropriate development of nervous system connectivity involves a variety of processes, including neuronal life-and-death decisions, differentiation, axon guidance and migration, and synaptogenesis. Although these activities likely require specialized signaling events, few substrates unique to these neurotrophic functions have been identified. Here we describe the cloning of ankyrin repeat-rich membrane spanning (ARMS), which encodes a novel downstream target of neurotrophin and ephrin receptor ...[more]

PMID: 11150334

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Project description:Significance statementMutations in hepatocyte nuclear factor-1 β ( HNF1B ) are the most common monogenic causes of congenital renal malformations. HNF1B is necessary to directly reprogram fibroblasts to induced renal tubule epithelial cells (iRECs) and, as we demonstrate, can induce ectopic pronephric tissue in Xenopus ectodermal organoids. Using these two systems, we analyzed the effect of HNF1B mutations found in patients with cystic dysplastic kidney disease. We found cross-species conserved targets of HNF1B, identified transcripts that are differentially regulated by the patient-specific mutant protein, and functionally validated novel HNF1B targets in vivo . These results highlight evolutionarily conserved transcriptional mechanisms and provide insights into the genetic circuitry of nephrogenesis.BackgroundHepatocyte nuclear factor-1 β (HNF1B) is an essential transcription factor during embryogenesis. Mutations in HNF1B are the most common monogenic causes of congenital cystic dysplastic renal malformations. The direct functional consequences of mutations in HNF1B on its transcriptional activity are unknown.MethodsDirect reprogramming of mouse fibroblasts to induced renal tubular epithelial cells was conducted both with wild-type HNF1B and with patient mutations. HNF1B was expressed in Xenopus ectodermal explants. Transcriptomic analysis by bulk RNA-Seq identified conserved targets with differentially regulated expression by the wild-type or R295C mutant. CRISPR/Cas9 genome editing in Xenopus embryos evaluated transcriptional targets in vivo .ResultsHNF1B is essential for reprogramming mouse fibroblasts to induced renal tubular epithelial cells and induces development of ectopic renal organoids from pluripotent Xenopus cells. The mutation R295C retains reprogramming and inductive capacity but alters the expression of specific sets of downstream target genes instead of diminishing overall transcriptional activity of HNF1B. Surprisingly, targets associated with polycystic kidney disease were less affected than genes affected in congenital renal anomalies. Cross-species-conserved transcriptional targets were dysregulated in hnf1b CRISPR-depleted Xenopus embryos, confirming their dependence on hnf1b .ConclusionsHNF1B activates an evolutionarily conserved program of target genes that disease-causing mutations selectively disrupt. These findings provide insights into the renal transcriptional network that controls nephrogenesis.

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An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors.

Publications

An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors.

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