Pitx2 regulates gonad morphogenesis

Abstract

Organ shape and size, and, ultimately, organ function, relate in part to the cell and tissue spatial arrangement that takes place during embryonic development. Despite great advances in the genetic regulatory networks responsible for tissue and organ development, it is not yet clearly understood how specific gene functions are linked to the specific morphogenetic processes underlying the internal organ asymmetries found in vertebrate animals. During female chick embryogenesis, and in contrast to males where both testes develop symmetrically, asymmetrical gonad morphogenesis results in only one functional ovary. The disposition of paired organs along the left-right body axis has been shown to be regulated by the activity of the homeobox containing gene pitx2. We have found that pitx2 regulates cell adhesion, affinity, and cell recognition events in the developing gonad primordium epithelia. This in turn not only allows for proper somatic development of the gonad cortex but also permits the proliferation and differentiation of primordial germ cells. We illustrate how Pitx2 activity directs asymmetrical gonad morphogenesis by controlling mitotic spindle orientation of the developing gonad cortex and how, by modulating cyclinD1 expression during asymmetric ovarian development, Pitx2 appears to control gonad organ size. All together our observations indicate that the effects elicited by Pitx2 during the development of the female chick ovary are critical for cell topology, growth, fate, and ultimately organ morphogenesis and function.cyclin D1 ͉ left-right asymmetry ͉ chick ovary development ͉ mitotic orientation ͉ primordial germ cell D espite the initial bilateral symmetry of the vertebrate body plan, internal organs, such as the heart, stomach, and intestines, all have a characteristic asymmetric structure and are asymmetrically positioned in the body cavity. The acquisition of proper left-right asymmetries is achieved in a highly conserved manner during embryo development. Since the seminal work more than a decade ago that identified a functional link between asymmetrical gene expression and organ asymmetry (1), our understanding of the molecular and cellular events involved in the establishment of left-right asymmetry in vertebrates has increased enormously. This is indeed the case in the initial establishment of left-right asymmetrical differences that occur during gastrulation as well as during the immediately subsequent stages of embryo development when the local asymmetrical cues in and around the node are deployed to broader domains of gene expression in the lateral plate mesoderm. Once side-specific gene expression domains are established and stabilized in the lateral plate mesoderm, left-right information is transferred to the organ primordial, where left and right side-specific morphogenetic programs are executed (reviewed in refs. 2-6).The identification of several genes that display side-specific patterns of expression within the developing organs has provided an entry point for understanding the molecu...

A right-sided pathway involving FGF8 / Snai1 controls asymmetric development of the proepicardium in the chick embryo

“…Nodal establishes a large expression domain in the left lateral plate mesoderm (LPM) and induces the expression of Pitx2, a homeobox gene of the bicoid class (7). Pitx2 determines morphological L-R asymmetries in most organ systems (9-12) via modulation of cell-cell adhesion, cell morphology, extracellular matrix composition, spindle orientation, and cell proliferation (13)(14)(15).…”

Advantages of the avian model for human ovarian cancer

“…Therefore, the higher prevalence of GCOC in the right ovary may be further elucidated by understanding the asymmetrical development of the gonads in the chicken. Regarding EOC, there is no evidence supporting a role for gonadal asymmetry in the prevalence of the disease in the right or left ovary (84); interestingly, however, paired-like homeodomain transcription factor 2 (PITX2), which is overexpressed in EOC, is also a key player in the asymmetric development of chicken female gonads (85,86). The expression of PITX2 in the left gonad promotes proliferation of the left cortex, leading to the asymmetric development of the gonads (85,87).…”

Left-Right Asymmetry in Chicken Embryonic Gonads

“…There is no further development of the right gonad and this leads to the formation of vestigial structures (Carlon and Stahl, 1985) or complete regression (Romanoff, 1960) at the adult stage. The molecular mechanism underlying asymmetrical development and the degeneration of the right ovary in female birds relies on PITX2 (Guioli and Lovell-Badge, 2007;Ishimaru et al, 2008;Rodriguez-Leon et al, 2008). Guioli and LovellBadge (2007) demonstrated that misexpression of Pitx2 in the right gonad using transfection with the RCAS retroviral vector is sufficient not only to induce symmetric development of the gonads but also to rescue the degeneration of the right ovary.…”

“…Pitx2-knockout mice have abnormalities of internal organ asymmetry (Lin et al, 1999;Lu et al, 1999). Recently, Pitx2 was reported to play a role in embryonic gonad asymmetry in both sexes (Guioli and LovellBadge, 2007;Ishimaru et al, 2008;Rodriguez-Leon et al, 2008).…”