Trends in Genetics
Volume 18, Issue 1, 1 January 2002, Pages 41-47
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Review
Getting your Pax straight: Pax proteins in development and disease

https://doi.org/10.1016/S0168-9525(01)02594-XGet rights and content

Abstract

The Pax gene family encodes a group of transcription factors that have been conserved through millions of years of evolution and play roles in early development. Pax proteins have been implicated as regulators of organogenesis and as key factors in maintaining pluripotency of stem cell populations during development. Mutations of the Pax genes cause profound developmental defects in organisms as diverse as flies, mice and humans. Here, we review crucial and illustrative roles of Pax gene products in cell-fate specification and developmental biology.

Section snippets

Modular structure of Pax proteins

Pax gene products are thought to function primarily by binding to enhancer DNA sequences and by modifying transcriptional activity of downstream genes. Structural analysis is consistent with this model because there are various domains within Pax proteins that can mediate DNA binding or transcriptional activation when isolated and assayed in vitro (Fig. 1). Recent evidence suggests that intramolecular interactions between distinct DNA-binding domains can modify activity and that Pax DNA-binding

Pax3 and neural crest

Studies in mouse and chick embryos demonstrate that Pax3 is synthesized in the dorsal neural tube, including the most dorsal regions from which the migratory population of neural crest cells emerge [20]. Neural crest cells migrate throughout the developing embryo and differentiate into many cell types including peripheral ganglia, enteric ganglia, melanocytes and Schwann cells. They contribute to multiple organs including the adrenal gland, thymus, parathyroid and the outflow tract of the

Pax3 and myogenesis

In addition to its role in neural crest cells, Pax3 is also crucial for the development of some skeletal muscle lineages. Skeletal muscles below the neck are derived from somites – segmented clusters of mesoderm that form on either side of the neural tube early during embryogenesis. Pax3 is expressed by presomitic mesoderm, and throughout the early epithelial somite. Later, its expression becomes restricted to the ventral–lateral domain of the elongating somites. These cells give rise to

Pax6 and eye development

Perhaps the most stunning observation confirming the role of Pax genes in organogenesis has come from the study of Pax6 and ocular development [42]. Pax6 is expressed in the forming optic cup and in the overlying ectoderm that will form the lens. Heterozygous PAX6 mutations in humans result in blindness, aniridia, colobomas and cataracts 15, 43. In mice, homozygous Pax6 deficiency results in complete absence of mature ocular structures [44]. Interestingly, missense mutations that affect the

Pax6, Pax4 and the endocrine pancreas

Within the pancreas, small clusters of endocrine cells are located among the more abundant exocrine tissue. Endocrine cells are clustered in islets and are capable of secreting crucial hormones, including insulin and glucagon, into the bloodstream. Specific deficiencies of islet cell types have been discovered in both Pax6- and Pax4-deficient mice. Pax6-deficient mice display complete loss of glucagon-producing α cells, and β, δ and γ cells fail to organize into proper spherical islets [51].

Pax5 and hematopoiesis

Blood and lymphoid cells are thought to arise from a self-renewing totipotent stem cell that gives rise to both myeloid and lymphoid precursor stem cells. Myeloid precursor cells give rise to basophils, eosinophils, neutrophils, macrophages, platelets and red blood cells. Lymphoid progenitor cells produce B cells, T cells and natural killer cells. The potential of a totipotent stem cell to differentiate into various hematopoietic cell types is progressively restricted under the influence of the

Pax2 and kidney development

Pax2 is expressed in the developing mouse kidney as well as the optic stalk, midbrain–hindbrain junction, and the spinal cord [60]. In the kidney, Pax2 is detected specifically in the caudal mesonephric duct, ureteric bud and later in mesenchymal condensates induced by the ureteric bud. At even later stages of nephrogenesis, Pax2 becomes restricted to the distal part of the S-shaped body, and gene expression is extinguished as cells differentiate.

Pax2 and Wilms tumor 1 (WT1) participate in an

Pax8 and thyroid development

In the thyroid, follicular cells that produce thyroxine arise from the thyroid diverticulum, whereas parafollicular cells that produce calcitonin derive from the neural crest. Pax8 expression has been observed in the thyroid diverticulum at E10.5 [67]. Pax8 homozygous deficient mice display dysgenesis of the thyroid gland including loss of all follicular cells [68]. Humans heterozygous for PAX8 mutations exhibit hypothyroidism [69]. Mutations identified in affected patients include missense

Pax1 and the skeleton

Pax1 and Pax9 are expressed in the developing vertebral column of the mouse embryo, in the limb buds, and in the embryonic and adult thymus 70, 71. Both genes also display overlapping expression patterns in the endodermally derived epithelium of the pharyngeal pouches, which develop into the thymus, parathyroid glands, ultimobranchial arches, eustachian tubes and tonsils. Pax9 is widely expressed in neural crest-derived mesenchyme involved in craniofacial and tooth formation 70, 71.

The undulated

Pax genes and cancer

Several chromosomal translocations involving members of the Pax gene family have been described in various human cancers, suggesting that altered regulation or transcriptional activity of Pax gene products can promote cellular transformation (reviewed in Ref. [76]). Pediatric alveolar rhabdomyosarcoma can result from a translocation between chromosomes 2 and 13 that results in the production of a fusion protein containing the DNA-binding domains of Pax3 and the potent transcriptional activation

Conclusions

Pax genes have emerged as important regulators of organogenesis in all species, with implications for the increased understanding and treatment of human disease. Ongoing studies suggest that these genes play important roles during multiple stages of development. These multiple functions, which include triggering differentiation processes as well as maintaining proliferative, pluripotent phenotypes, suggest a diversity of activity at the cellular level. This diversity is mirrored at the

Acknowledgements

Fig. 1 was drawn by Nicole Boitos. We apologize to our colleagues for the absence of many important references due to space restrictions. This work was supported by grants from the NIH (HL62974, HL61475), AHA and the WW Smith Foundation.

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