Developmental changes in the human GH receptor and its signal transduction pathways.
We previously reported the presence of functional human GH receptors (hGHRs) in the human fetal hepatocyte (FH) as early as the first trimester. Interestingly, fetal serum levels of hGH are in the acromegalic range, yet certain hGH-dependent factors are expressed at very low levels (IGF-I, IGF-binding protein-3), suggesting that fetal liver has limited responsiveness to hGH. To determine whether this is due to the fetal tissue levels of hGHR or factors in the hGH/hGHR axis that might influence hGHR function, we compared hGHR isoforms and downstream signaling proteins in FH versus human adult liver (HAL). Immunoprecipitation/immunoblotting (IB) analyses found similar precursor and mature hGHR forms while RT-PCR assays of truncated (T) hGHR(1-279), dominant negative for the full-length (FL) receptor, showed similar T/FL mRNA ratios in FH and HAL. IB demonstrated that Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT(1, 3, 5A/B)), and suppressors of cytokine signaling (SOCS(1, 2, 3, cytokine-inducible SH2-containing protein (CIS))) proteins were detectable in all FH and HAL tested (12 weeks of fetal age to 60 years); the levels were similar (STAT5B) or lower (JAK2/STAT1/STAT3/STAT5A: 38-53%, SOCS/CIS: 58-76%) in FH compared with HAL. Our studies to date demonstrate that, during hepatocyte development, hGHR levels are lower in the fetal cells but the hGHR isoforms, including the relative amount of truncated versus FL, remain unchanged. The JAK2/STAT/SOCS signaling molecules are present in the FH as early as the first trimester. However, they are generally at <50% level in postnatal liver. These data suggest that low expression of both hGHR and major hGHR signaling components may explain the limited responsiveness of the fetal cells to the high circulating levels of hGH.
Kenth
Gurvinder
G
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Mergelas
Jennifer A Manalo
JA
Goodyer
Cynthia Gates
CG
D000818:Animals; D002460:Cell Line; D005333:Fetus / Q000737:chemistry*; D022781:Hepatocytes / Q000737:chemistry; D006801:Humans; D053614:Janus Kinase 2 / Q000032:analysis / Q000502:physiology; D008099:Liver / Q000737:chemistry; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D050791:STAT Transcription Factors / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000502:physiology
D008565:Membrane Proteins; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; C405010:delta-hGHR; C507924:JAK2 protein, human; D053614:Janus Kinase 2