Mechanisms and pathways of growth failure in primordial dwarfism.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK.
The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
- PMID: 21979914 [PubMed – indexed for MEDLINE] PMCID: PMC319720
(A) Cell size and cell number determine organism size. Conceptually, body size can be altered through reducing the number of cell divisions or reducing cell size. For example, if during an identical period of development, cells divide only five times out of the usual seven rounds of cell division, this will reduce body volume by 75%. Reducing cell volume to a quarter of normal could similarly reduce body size while maintaining cell number constant. (B) In mammals, body size appears to be predominantly determined by cell number. There is a 3000-fold difference in body mass between mice (25 g) and humans (70 kg), while volume of cells from similar tissues remains relatively unchanged (Conlon and Raff 1999). (C) Cell number can be increased in mammals through alterations in proliferation kinetics. For instance, transgenic expression of stabilized β-catenin protein enlarges brain size in mice during embryogenesis. Midcoronal sections through the embryonic day 15.5 (E15.5) cerebral cortex from a control mouse embryo (left) and a mouse with the Δ90β-catenin-GFP transgene expressed in neural precursors, resulting in an enlarged brain with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. Bar, 1 mm. (Image from Chenn and Walsh 2002. Reprinted with permission from AAAS.)
- Figure 2.
Intracellular signaling pathways regulating growth. PI3K/TOR, Hippo, and MAPK pathways regulate growth by modulating protein translation, cell cycle progression, and apoptosis. Schematic of pathways showing key components. Genes highlighted in red are mutated in human genetic syndromes that manifest growth deficiency or overgrowth. (A) Growth hormone acts systemically through its regulation of IGF-1, which activates phosphotidyl-inosine-3 kinase (PI3K) by binding the IGF-1 receptor (IGF-1R). Subsequent activation of downstream kinases results in increased protein translation and ribosome biosynthesis, leading to cellular growth. The pathway is inhibited by the phosphatase PTEN and integrates multiple other signals, such as nutrient/energy levels, through the master kinase target of rapamycin (TOR). TOR activates the ribosomal S6 kinase and facilitates eIF4E activity to promote translation and transcription initiation. (B) The Hippo pathway restricts growth to control organ size and prevent tissue overgrowth and tumorigenesis. The pathway is currently best defined in Drosophila, where the cell polarity protein Crumbs (Crb) and the protocadherins Fat and Dachsous (Ds) activate Hippo kinase, which in turn activates Warts kinase. The signaling cascade negatively regulates the transcriptional coactivator Yorkie (Yki) by retaining Yki in the cytoplasm. This restricts cell proliferation and promotes cell death, as Yki promotes G1 progression over G0 cell cycle exit through transcriptional up-regulation of Cyclin E (CycE) and the E2F transcription factor. Yki also has an anti-apoptotic effect by inducing inhibitor of apoptosis protein (IAP). The core pathway is conserved in mammals: Mst1/2 (Hippo), Lats (Warts), and Yap (Yki). Homologs to Fat and Ds or the target gene bantam have not yet been identified in mammals. (C) The MAPK (ERK) signaling cascade transduces mitogen signals, driving cellular proliferation by promoting G1-to-S-phase progression (Meloche and Pouysségur 2007). Downstream, ERK kinase activates the proproliferative transcription factors Myc and E2F as well as decreases levels of the cyclin-dependent kinase inhibitors p21 and p27. Rather than being entirely discrete signaling pathways, these three signaling pathways (A–C) overlap; for instance, Akt inhibits Hippo activity, while ERK phosphorylates, and thus activates, TOR.