1: Kidney Int. 2005 Nov;68(5):1964. 

GZF1, a new GDNF-inducible gene, is required for renal branching morphogenesis.

Fukuda N, Morinaga T, Matsuo S.

Division of Clinical Immunology, Department of Internal Medicine, Nagoya
University Graduate School of Medicine, Nagoya, Japan.

The glial cell line-derived neurotrophic factor (GDNF)/ rearrangement during
transfection, tyrosine kinase (RET) signaling is recognized as a critical
pathway of renal branching morphogenesis, and much attention has been paid to
the molecules that function upstream of this pathway. It was suggested that
transcription factors, Pax2 and Eya-1, are responsible for Gdnf expression, and
Foxc1 prevents ectopic ureteric budding from Wolffian duct by repressing Gdnf
and Eya1. In addition, vitamin A signal from stromal mesenchyme is necessary for
Ret expression. Recently it was reported that Wnt11 and Sprouty proteins are
associated with the GDNF/RET signaling, but the detailed process downstream of
the GDNF/RET signaling in renal development is still poorly understood. We
performed an exhaustive analysis of GDNF-inducible genes by differential display
to identify an important molecule which function downstream of the GDNF/RET
signaling pathway. As a consequence, we found the increased expression of 14
genes by GDNF. Among them, we focused on a new gene with a BTB/POZ domain and
C2H2-type zinc finger motifs that was named GZF1 (GDNF-inducible zinc finger
gene 1). To elucidate the importance of GZF1 on kidney development, we stained
the mouse embryonic kidney with anti-GZF1 antibody. Interestingly, the ureteric
bud epithelia of embryonic metanephroi were strongly stained, whereas S-shaped
or comma-shaped bodies were not stained. Using serial sections, we detected the
expression of GZF1 and RET in the same ureteric buds. Furthermore, antisense
oligonucleotides (ODNs) of the Gzf1 markedly impaired the ureteric bud branching
in the metanephric organ culture, suggesting that the induction of GZF1 via the
GDNF/RET signaling system is required for renal branching morphogenesis. We
investigated the transcriptional activity of GZF1 by luciferase reporter gene
assay. In this assay, it was revealed that the GZF1 possesses transcriptional
repressive activity. To examine the binding sequence for GZF1, we employed
cyclic amplification and selection of targets (CASTing). Finally, a consensus
sequence was derived from the sequence alignment of individual clones. We named
it GZF1 recognition element (GRE). Next we searched for potential target genes
that might be regulated by GZF1 and found that a variety of genes possess the
GRE in their 5' upstream regulatory region. We are now investigating the effect
of the GRE on the promoter activity of one gene among them. To examine whether
the GZF1 binds the promoter region of this gene, we performed modified chromatin
immunoprecipitation assay. It was shown that GZF1 binds the promoter region of
this gene. Further analysis about the transcriptional effect of GZF1 on this
gene is now moving. As described above, this novel gene GZF1 may play a crucial
role in renal development regulated by the GDNF/RET signaling. We are now
generating Gzf1(-/-) mouse. We expect this novel molecule will promote our
understanding of the mechanisms of the renal organogenesis. Furthermore, its
clinical application to the treatment of renal disease, especially to the
regeneration of the kidney, should be explored in the future.

PMID: 16221181 [PubMed - in process]


---------------------------------------------------------------


2: Pediatr Nephrol. 2004 Mar;19(3):249-55. Epub 2003 Dec 13. 

Genetic determination of nephrogenesis: the Pax/Eya/Six gene network.

Brodbeck S, Englert C.

Development of the kidney serves as a paradigm to understand the mechanisms
underlying the formation of an organ. The first sign of kidney development is
the interaction between two tissues derived from the intermediate mesoderm, the
metanephrogenic mesenchyme and the nephric duct. Many of the genes that play a
crucial role in early kidney development, such as Pax2, Eya1, Six1, Six2, Sall1,
Foxc1, Wt1, and the Hox11 genes, are expressed in the mesenchyme and encode
transcription factors that--with few exceptions--are involved in regulation of
the Gdnf gene. Moreover, mutations in a number of these genes in humans are
associated with kidney diseases. Interestingly, many of the components
regulating early kidney development are conserved throughout evolution and are
also involved in eye and muscle formation in mammals, as well as in eye
development in Drosophila. Genetic and biochemical studies in Drosophila and
mice indicate that these genes and their respective products act in a complex
network of interdependencies and positive and negative feedback loops. Genetic
experiments have allowed us to begin to characterize the complex interactions
between the individual components, but it will require additional biochemical
and functional experiments to eventually understand the molecular functions of
each of the participating proteins.

Publication Types:
    Editorial
    Review

PMID: 14673635 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------