Regulation of body growth

Abstract

Purpose of review: Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new molecular defects that cause growth failure and overgrowth, and genome-wide association studies have elucidated the genetic basis for normal human height variation.

Recent findings: The Hippo pathway has emerged as one of the major mechanisms controlling organ size. In addition, an extensive genetic program has been described that allows rapid body growth in the fetus and infant but then causes growth to slow with age in multiple tissues. In human genome-wide association studies, hundreds of loci associated with adult stature have been identified; many appear to involve genes that function locally in the growth plate. Clinical genetic studies have identified a new genetic abnormality, microduplication of Xq26.3, that is responsible for growth hormone excess, and a gene, DNMT3A, in which mutations cause an overgrowth syndrome through epigenetic mechanisms.

Summary: These recent advances in our understanding of somatic growth not only provide insight into childhood growth disorders but also have broader medical applications because disruption of these regulatory systems contributes to oncogenesis.

Fig 1.. Mammalian Hippo signaling pathway regulates organ growth.

The mammalian homologues of Drosophila Hippo (Hpo) are called MST1 kinase and MST2 kinase. Close to the cytoplasmic membrane, MST1/2 forms an active complex with WW repeat scaffolding protein WW45 (or Salvador in Drosophila). MST/WW45 complex then phosphorylates nuclear DBF-2-related kinase LATS1/2 (or Wts in Drosophila) with the help of another tumor suppressor Merlin/NF2, which is required for the recruitment of LATS1/2 to the cytoplasmic membrane. LATS in turn interacts with MOB to phosphorylate transcriptional coactivators YAP and TAZ (or Yorkie in Drosophila), causing inactivation excluion from the nucleus, and downregulation of genes important for cell cycle progressive, proliferation and organ growth.

Fig 2.. Sequence variants in genes that affect growth plate function can produce a broad phenotypic spectrum.

For genes that positive regulate growth plate function, severe loss-of-function mutations often present as a skeletal dyplasias whereas milder mutations may present as short stature without an overt dysplasia. Common polymorphisms can modulate height, and gain-of-function mutations can cause tall stature.