Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens

Zheng Z. Liu, Jun Wada, Anil Kumar, Frank A. Carone, Masahide Takahashi, Yashpal S. Kanwar

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Receptor-like protooncogenes, with tyrosine kinase catalytic domains, are expressed in neoplastic and fetal tissues and potentially have a role in embryonic development. Which protooncogene may have the dominant role in embryonic renal development during the 'postinductive' period, i.e., Day 10 onward, was addressed in this study by utilizing an in vitro organ culture system. The role of various receptor-like protooncogenes, with the emphasis on c-ros and c-ret, was investigated by antisense-oligodeoxynucleotide (ODN) gene-targeting strategies at a point in metanephric development when reciprocal-inductive interactions between the epithelium and mesenchyme have already been initiated and are rampant. Also, their relationship with other morphogens, like extracellular matrix (ECM) proteins and growth factors, was studied. Initial in situ hybridization and RT-PCR analyses revealed a similar spatiotemporal expression for both c-ros and c-ret in the embryonic kidneys. At Day 13, they were mainly expressed in the developing nephrons in the nephrogenic zone and ureteric bud branches, where the signals from the mesenchymal ligands are transduced to the epithelial cell surface receptors. Minimal expression was observed in the newborn kidneys. Inclusion of antisense ODNs, derived from the phosphotyrosine kinase domains, inhibited metanephric growth in the organ culture; the most dramatic effects were observed with the c-ret antisense ODN. The c-ret-induced dysmorphogenetic effects were characterized as a decrease in the population of nephrons, atrophy of the mesenchymal cells, and loss of acuteness of the tips of ureteric bud branches. Interestingly, the ureteric bud branches continue to grow in the atrophic mesenchyme. Both c-ros and c-ret antisense ODNs reduced the gene expression and biosynthesis of various ECM proteins. The proteoglycans, expressed at the epithelial:mesenchymal interface, were most adversely affected, especially by the c-ret antisense. The treatment of metanephric explants with c-ret did not affect the gene expression of c-ros and vice versa. The specificity of the effects of c-ret antisense was also reflected by a decrease of anti-Ret protein immunoreactivity. The studies were extended to establish a relationship between c-ret protooncogene and some of the growth factors which are known to influence renal development via their tyrosine kinase-like receptors localized in the ureteric bud branches, the site apparently where c-ret is also expressed. Among the various growth factors examined, transforming growth factor-α (TGF-α) and insulin like growth factor-I (IGF-I) had the most notable trophic effects on metanephric explants and caused maximal phosphorylation of Ret protein. In addition, concurrent exposure of TGF-α or IGF-I and c-ret antisense ODN explants caused partial recovery from the c-ret-induced dysmorphogenetic effects in the metanephroi. The data suggest that, although a number of protooncogenes share similar catalytic domains, c-ret plays a major role during the 'postinductive' period of metanephric development by perturbing the growth factor-dependent expression of ECM morphogenetic macromolecules, notably that of the proteoglycans, and also by affecting certain yet undefined growth factor-mediated phosphorylation mechanism(s) involving c-ret.

Original languageEnglish
Pages (from-to)133-148
Number of pages16
JournalDevelopmental Biology
Volume178
Issue number1
DOIs
Publication statusPublished - Aug 25 1996
Externally publishedYes

Fingerprint

Phosphotyrosine
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Oligodeoxyribonucleotides
Kidney
Extracellular Matrix Proteins
Organ Culture Techniques
Nephrons
Transforming Growth Factors
Mesoderm
Proteoglycans
Insulin-Like Growth Factor I
Embryonic Development
Catalytic Domain
Phosphorylation
Gene Expression
Gene Targeting
Population Dynamics
Receptor Protein-Tyrosine Kinases
Cell Surface Receptors

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens. / Liu, Zheng Z.; Wada, Jun; Kumar, Anil; Carone, Frank A.; Takahashi, Masahide; Kanwar, Yashpal S.

In: Developmental Biology, Vol. 178, No. 1, 25.08.1996, p. 133-148.

Research output: Contribution to journalArticle

Liu, Zheng Z. ; Wada, Jun ; Kumar, Anil ; Carone, Frank A. ; Takahashi, Masahide ; Kanwar, Yashpal S. / Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens. In: Developmental Biology. 1996 ; Vol. 178, No. 1. pp. 133-148.
@article{c329e10a48c6449fb4bd1607b302d94e,
title = "Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens",
abstract = "Receptor-like protooncogenes, with tyrosine kinase catalytic domains, are expressed in neoplastic and fetal tissues and potentially have a role in embryonic development. Which protooncogene may have the dominant role in embryonic renal development during the 'postinductive' period, i.e., Day 10 onward, was addressed in this study by utilizing an in vitro organ culture system. The role of various receptor-like protooncogenes, with the emphasis on c-ros and c-ret, was investigated by antisense-oligodeoxynucleotide (ODN) gene-targeting strategies at a point in metanephric development when reciprocal-inductive interactions between the epithelium and mesenchyme have already been initiated and are rampant. Also, their relationship with other morphogens, like extracellular matrix (ECM) proteins and growth factors, was studied. Initial in situ hybridization and RT-PCR analyses revealed a similar spatiotemporal expression for both c-ros and c-ret in the embryonic kidneys. At Day 13, they were mainly expressed in the developing nephrons in the nephrogenic zone and ureteric bud branches, where the signals from the mesenchymal ligands are transduced to the epithelial cell surface receptors. Minimal expression was observed in the newborn kidneys. Inclusion of antisense ODNs, derived from the phosphotyrosine kinase domains, inhibited metanephric growth in the organ culture; the most dramatic effects were observed with the c-ret antisense ODN. The c-ret-induced dysmorphogenetic effects were characterized as a decrease in the population of nephrons, atrophy of the mesenchymal cells, and loss of acuteness of the tips of ureteric bud branches. Interestingly, the ureteric bud branches continue to grow in the atrophic mesenchyme. Both c-ros and c-ret antisense ODNs reduced the gene expression and biosynthesis of various ECM proteins. The proteoglycans, expressed at the epithelial:mesenchymal interface, were most adversely affected, especially by the c-ret antisense. The treatment of metanephric explants with c-ret did not affect the gene expression of c-ros and vice versa. The specificity of the effects of c-ret antisense was also reflected by a decrease of anti-Ret protein immunoreactivity. The studies were extended to establish a relationship between c-ret protooncogene and some of the growth factors which are known to influence renal development via their tyrosine kinase-like receptors localized in the ureteric bud branches, the site apparently where c-ret is also expressed. Among the various growth factors examined, transforming growth factor-α (TGF-α) and insulin like growth factor-I (IGF-I) had the most notable trophic effects on metanephric explants and caused maximal phosphorylation of Ret protein. In addition, concurrent exposure of TGF-α or IGF-I and c-ret antisense ODN explants caused partial recovery from the c-ret-induced dysmorphogenetic effects in the metanephroi. The data suggest that, although a number of protooncogenes share similar catalytic domains, c-ret plays a major role during the 'postinductive' period of metanephric development by perturbing the growth factor-dependent expression of ECM morphogenetic macromolecules, notably that of the proteoglycans, and also by affecting certain yet undefined growth factor-mediated phosphorylation mechanism(s) involving c-ret.",
author = "Liu, {Zheng Z.} and Jun Wada and Anil Kumar and Carone, {Frank A.} and Masahide Takahashi and Kanwar, {Yashpal S.}",
year = "1996",
month = "8",
day = "25",
doi = "10.1006/dbio.1996.0204",
language = "English",
volume = "178",
pages = "133--148",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens

AU - Liu, Zheng Z.

AU - Wada, Jun

AU - Kumar, Anil

AU - Carone, Frank A.

AU - Takahashi, Masahide

AU - Kanwar, Yashpal S.

PY - 1996/8/25

Y1 - 1996/8/25

N2 - Receptor-like protooncogenes, with tyrosine kinase catalytic domains, are expressed in neoplastic and fetal tissues and potentially have a role in embryonic development. Which protooncogene may have the dominant role in embryonic renal development during the 'postinductive' period, i.e., Day 10 onward, was addressed in this study by utilizing an in vitro organ culture system. The role of various receptor-like protooncogenes, with the emphasis on c-ros and c-ret, was investigated by antisense-oligodeoxynucleotide (ODN) gene-targeting strategies at a point in metanephric development when reciprocal-inductive interactions between the epithelium and mesenchyme have already been initiated and are rampant. Also, their relationship with other morphogens, like extracellular matrix (ECM) proteins and growth factors, was studied. Initial in situ hybridization and RT-PCR analyses revealed a similar spatiotemporal expression for both c-ros and c-ret in the embryonic kidneys. At Day 13, they were mainly expressed in the developing nephrons in the nephrogenic zone and ureteric bud branches, where the signals from the mesenchymal ligands are transduced to the epithelial cell surface receptors. Minimal expression was observed in the newborn kidneys. Inclusion of antisense ODNs, derived from the phosphotyrosine kinase domains, inhibited metanephric growth in the organ culture; the most dramatic effects were observed with the c-ret antisense ODN. The c-ret-induced dysmorphogenetic effects were characterized as a decrease in the population of nephrons, atrophy of the mesenchymal cells, and loss of acuteness of the tips of ureteric bud branches. Interestingly, the ureteric bud branches continue to grow in the atrophic mesenchyme. Both c-ros and c-ret antisense ODNs reduced the gene expression and biosynthesis of various ECM proteins. The proteoglycans, expressed at the epithelial:mesenchymal interface, were most adversely affected, especially by the c-ret antisense. The treatment of metanephric explants with c-ret did not affect the gene expression of c-ros and vice versa. The specificity of the effects of c-ret antisense was also reflected by a decrease of anti-Ret protein immunoreactivity. The studies were extended to establish a relationship between c-ret protooncogene and some of the growth factors which are known to influence renal development via their tyrosine kinase-like receptors localized in the ureteric bud branches, the site apparently where c-ret is also expressed. Among the various growth factors examined, transforming growth factor-α (TGF-α) and insulin like growth factor-I (IGF-I) had the most notable trophic effects on metanephric explants and caused maximal phosphorylation of Ret protein. In addition, concurrent exposure of TGF-α or IGF-I and c-ret antisense ODN explants caused partial recovery from the c-ret-induced dysmorphogenetic effects in the metanephroi. The data suggest that, although a number of protooncogenes share similar catalytic domains, c-ret plays a major role during the 'postinductive' period of metanephric development by perturbing the growth factor-dependent expression of ECM morphogenetic macromolecules, notably that of the proteoglycans, and also by affecting certain yet undefined growth factor-mediated phosphorylation mechanism(s) involving c-ret.

AB - Receptor-like protooncogenes, with tyrosine kinase catalytic domains, are expressed in neoplastic and fetal tissues and potentially have a role in embryonic development. Which protooncogene may have the dominant role in embryonic renal development during the 'postinductive' period, i.e., Day 10 onward, was addressed in this study by utilizing an in vitro organ culture system. The role of various receptor-like protooncogenes, with the emphasis on c-ros and c-ret, was investigated by antisense-oligodeoxynucleotide (ODN) gene-targeting strategies at a point in metanephric development when reciprocal-inductive interactions between the epithelium and mesenchyme have already been initiated and are rampant. Also, their relationship with other morphogens, like extracellular matrix (ECM) proteins and growth factors, was studied. Initial in situ hybridization and RT-PCR analyses revealed a similar spatiotemporal expression for both c-ros and c-ret in the embryonic kidneys. At Day 13, they were mainly expressed in the developing nephrons in the nephrogenic zone and ureteric bud branches, where the signals from the mesenchymal ligands are transduced to the epithelial cell surface receptors. Minimal expression was observed in the newborn kidneys. Inclusion of antisense ODNs, derived from the phosphotyrosine kinase domains, inhibited metanephric growth in the organ culture; the most dramatic effects were observed with the c-ret antisense ODN. The c-ret-induced dysmorphogenetic effects were characterized as a decrease in the population of nephrons, atrophy of the mesenchymal cells, and loss of acuteness of the tips of ureteric bud branches. Interestingly, the ureteric bud branches continue to grow in the atrophic mesenchyme. Both c-ros and c-ret antisense ODNs reduced the gene expression and biosynthesis of various ECM proteins. The proteoglycans, expressed at the epithelial:mesenchymal interface, were most adversely affected, especially by the c-ret antisense. The treatment of metanephric explants with c-ret did not affect the gene expression of c-ros and vice versa. The specificity of the effects of c-ret antisense was also reflected by a decrease of anti-Ret protein immunoreactivity. The studies were extended to establish a relationship between c-ret protooncogene and some of the growth factors which are known to influence renal development via their tyrosine kinase-like receptors localized in the ureteric bud branches, the site apparently where c-ret is also expressed. Among the various growth factors examined, transforming growth factor-α (TGF-α) and insulin like growth factor-I (IGF-I) had the most notable trophic effects on metanephric explants and caused maximal phosphorylation of Ret protein. In addition, concurrent exposure of TGF-α or IGF-I and c-ret antisense ODN explants caused partial recovery from the c-ret-induced dysmorphogenetic effects in the metanephroi. The data suggest that, although a number of protooncogenes share similar catalytic domains, c-ret plays a major role during the 'postinductive' period of metanephric development by perturbing the growth factor-dependent expression of ECM morphogenetic macromolecules, notably that of the proteoglycans, and also by affecting certain yet undefined growth factor-mediated phosphorylation mechanism(s) involving c-ret.

UR - http://www.scopus.com/inward/record.url?scp=0030601360&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030601360&partnerID=8YFLogxK

U2 - 10.1006/dbio.1996.0204

DO - 10.1006/dbio.1996.0204

M3 - Article

C2 - 8812115

AN - SCOPUS:0030601360

VL - 178

SP - 133

EP - 148

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

IS - 1

ER -