Prox1 is a prospero-related homeobox gene in mouse (Oliver, 1993).

The genomic organization and nucleotide sequence of the human homeobox gene Prox 1 as well as its chromosomal localization have been determined. This gene spans more than 40 kb, consists of at least 5 exons, and encodes an 83-kDa protein. It shows 89% identity with the chicken sequence at the nucleotide level in the coding region, while the human and chicken proteins are 94% identical. Among the embryonic tissues analyzed (lens, brain, lung, liver, and kidney), the human Prox 1 gene is most actively expressed in the developing lens, similar to the expression pattern of the chicken Prox 1 gene. The Prox 1 gene was mapped to human chromosome 1q32.2-q32.3 (Zinovieva, 1996).

The alpha-globin major regulatory element (alpha MRE) positioned far upstream of the gene cluster is essential for the proper expression of the alpha-globin genes. Analysis of the human and mouse alpha-globin upstream flanking regions (alpha UFR) has identified three nonglobin genes in the order Dist1-MPG-Prox1-alpha-globin. Further characterization of the whole region indicates that the alpha MRE and several other erythroid DNase HSSs are associated with the transcription unit of the Prox1 gene. In this paper the characterization and localization of the mouse Prox1 cDNA is described and it is compared with its human homolog, the -14 gene, and another human cDNA sequence named hProx1. There is a strong conservation between the -14 gene and the mouse Prox1 gene with the exception of the first exon of the mProx1 gene. This exon is absent in the -14 cDNA but is present and conserved in the human Prox1 cDNA, indicating that the human -14/hProx1 gene is alternatively spliced or transcribed. The mProx1 gene encodes a predicted protein of 491 amino acids (aa) whose function is not known. In the 5'UTR of this gene, a 35-bp repeat (VNTR) is positioned, which is highly polymorphic among laboratory inbred mice (Mus domesticus). These results strongly suggest that the mProx1 VNTR arose during the divergence of M. spretus and M. domesticus. In addition to its use in evolutionary studies and positional cloning, the mProx1 VNTR might be invaluable for monitoring the expression of a transgenic mProx1 gene. The cloning of the mProx1 gene will be helpful to analyze its possible role on alpha-globin as well on MPG expression in the mouse (Kielman, 1996).

Prox 1 is the vertebrate homolog of Drosophila prospero, a gene known to be expressed in the lens-secreting cone cells of fly ommatidia. Chicken Prox 1 cDNAs were isolated from 14 day embryonic chicken lenses, and a complete open reading frame encoding an 83 kDa protein was elucidated. The homeodomains of chicken and mouse Prox 1 are identical at the amino acid level and are 65%-67% similar to the homeodomains of Drosophila and C. elegans prospero. The homology between these proteins extends beyond the homeodomain. There is 56% identity between chicken Prox 1 and Drosophila prospero in the C-terminal region downstream of the homeodomain, whereas there is little similarity upstream of the homeodomain. Prox 1 is expressed most actively in the developing lens and midgut and at lower levels in the developing brain, heart, muscle, and retina. cDNA sequencing has established that there are alternatively spliced forms of the single Prox 1 gene, which probably account for the two abundant RNAs of about 2 and 8 kb and two less abundant RNAs close to 3.5 kb in length in the lens. In the lens fibers, only the shortest mRNA is present, whereas, in the epithelial cells, both short and long mRNAs are detected. By using in situ hybridization, expression of the Prox 1 gene is first detected at stage 14 in the early lens placode, slightly preceding the expression of delta 1-crystallin, the first crystallin gene expressed in the developing chicken lens. At later stages of development, Prox 1 mRNA is observed throughout the lens, but it appears more abundant around the bow region of the equator than in the anterior epithelium or the fibers. In the retina, expression of the Prox 1 gene is detected mainly in the inner nuclear layer during later stages of histogenesis. The conserved pattern of Prox 1/prospero gene expression in vertebrates and Drosophila suggests that Prox 1, like Pax-6, may be essential for eye development in different systematic groups (Tomarev, 1996).

Prox1, a vertebrate homolog of Drosophila prospero, encodes a divergent homeodomain protein. Full length mouse Prox1 cDNA and genomic clones have been isolated and characterized. Mouse Prox1 gene maps to position 106.3 cM from the centromere of Chromosome 1, which is very close to the retinal degeneration mutation, rd3. Although the coding sequence and exon-intron junctions of the Prox1 genes of wild type and rd3 mutant mice are identical, Northern blot analysis indicates that the ratio of the short (2.3 kb) and long (8 kb) forms of Prox1 mRNA is different in RNA isolated from wild type and rd3 retinas. Immunostaining of the eyes from wild type and rd3 animals also reveal differences in the distribution of Prox1 protein in the retina and lens. These data suggest that the rd3 mutation affects expression of the mouse Prox1 gene (Tomarev, 1998).

A prox 1 cDNA from zebrafish has been isolated that encodes a protein that has 82%, 84% and 83% amino acid identity with chicken, mouse and human Prox 1, respectively. Antibodies raised against human Prox 1 cross-react with zebrafish Prox 1 and were used to determine the expression patterns of Prox 1 during zebrafish embryogenesis by whole-mount immunohistochemistry. In the 10-somite embryo, Prox 1 is expressed over the prospective lens placode and over a broad region of epithelium extending from the eye to the otic vesicle. As embryogenesis proceeds, Prox 1 expression in the eye lens becomes intense, and is detected in maturing muscle pioneer cells and superficial muscle cells. In the CNS, Prox 1 is expressed in a stripe along the forebrain-midbrain boundary, in a segmented pattern in the ventral hindbrain, and in selected cells of the ventral spinal cord. Additional sites of Prox 1 expression include the lateral line primordium, the trigeminal ganglia, the otic vesicle and occasional endodermal cells (Glasgow, 1998).

Expression of the homeobox gene Prox 1 has been examined during eye degeneration and sensory organ compensation in cavefish embryos. The teleost Astyanax mexicanus consists of sighted surface-dwelling forms (surface fish) and several populations of blind cave-dwelling forms (cavefish), which have evolved independently. Eye formation is initiated during cavefish development, but the lens vesicle undergoes apoptosis, and the eye subsequently arrests and degenerates. The requirement of Prox 1 for lens fiber differentiation and gamma-crystallin expression in the mouse suggests that changes in the expression of this gene could be involved in cavefish eye degeneration. Surface fish and cavefish embryos stained with a Prox 1 antibody show Prox 1 expression in the lens, neuroretina, myotomes, heart, hindbrain, and gut, as reported in other vertebrates. Prox 1 expression is not altered during cavefish lens development. Prox 1 protein is detected in the lens vesicle as soon as it forms and persists until the time of lens degeneration in each cavefish population. The cavefish lens vesicle has also been shown to express a gamma-crystallin gene, suggesting that Prox 1 is functional in cavefish lens development. In addition to the tissues described above, in cavefish Prox 1 is expressed in developing taste buds and neuromasts, which are enhanced to compensate for blindness. It is concluded that the Prox1 gene is not involved in lens degeneration, but that expansion of the Prox 1 expression domain occurs during taste bud and neuromast development in cavefish (Jeffery, 2000).

This is the first report of Prox 1 expression in taste buds and suggests that this gene is involved in gustatory system development. Only a few other regulatory genes, namely Dlx-3, sonic hedgehog, patched, and Gli1, are currently known to be expressed during taste bud development. The discovery of Prox 1 expression in taste buds suggests that this gene is an early marker of taste bud development. These results indicate that Prox 1 is expressed in the taste receptor cells of taste buds. Although it was once believed that the taste receptor cells are induced by underlying sensory neurons, it has recently been shown that these cells develop intrinsically from local oropharyngeal epithelium and are instead likely to attract neural elements as targets. In Drosophila, the Prox 1 homolog prospero regulates the fate of developing neural cells by a lateral specification mechanism involving the Notch gene. Therefore, Prox 1 expression in taste bud primordia suggests that the vertebrate gustatory system also may be patterned by a lateral specification process (Jeffery, 2000).

Although insights have emerged regarding genes controlling the early stages of eye formation, little is known about lens-fiber differentiation and elongation. The expression pattern of Prox1, a prospero related homeobox gene, suggests it has a role in a variety of embryonic tissues, including lens. To analyse the requirement for Prox1 during mammalian development, the locus was inactivated in mice. Homozygous Prox1-null mice die at mid-gestation from multiple developmental defects; the specific effect on lens development is described. Prox1 inactivation causes abnormal cellular proliferation, downregulated expression of the cell-cycle inhibitors Cdkn1b (also known as p27KIP1) and Cdkn1c (also known as p57KIP2), misexpression of E-cadherin, and inappropriate apoptosis. Consequently, mutant lens cells fail to polarize and elongate properly, resulting in a hollow lens. These data provide evidence that the progression of terminal fiber differentiation and elongation is dependent on Prox1 activity during lens development (Wigle, 1999).

The process of angiogenesis has been well documented, but little is known about the biology of lymphatic endothelial cells and the molecular mechanisms controlling lymphangiogenesis. The homeobox gene Prox1 is expressed in a subpopulation of endothelial cells that, after budding from veins, gives rise to the mammalian lymphatic system. In Prox1-/- embryos, this budding becomes arrested at around embryonic day (E)11.5, resulting in embryos without lymphatic vasculature. Unlike the endothelial cells that bud off in E11.5 wild-type embryos, those of Prox1-null embryos do not co-express any lymphatic markers such as VEGFR-3, LYVE-1 or SLC. Instead, the mutant cells appear to have a blood vascular phenotype, as determined by their expression of laminin and CD34. These results suggest that Prox1 activity is required for both maintenance of the budding of the venous endothelial cells and differentiation toward the lymphatic phenotype. On the basis of these findings, it is proposed that a blood vascular phenotype is the default fate of budding embryonic venous endothelial cells; upon expression of Prox1, these budding cells adopt a lymphatic vasculature phenotype (Wigle, 2002).

Early during development, one of the first indications that lymphangiogenesis has begun is the polarized expression of the homeobox gene Prox1 in a subpopulation of venous endothelial cells. Prox1 expression in the cardinal vein promotes and maintains the budding of endothelial cells that will form the lymphatic vascular system. Prox1-deficient mice are devoid of lymphatic vasculature, and in these animals endothelial cells fail to acquire the lymphatic phenotype; instead, they remain as blood vascular endothelium. To investigate whether Prox1 is sufficient to induce a lymphatic fate in blood vascular endothelium, Prox1 cDNA was ectopically expressed by adenoviral gene transfer in primary human blood vascular endothelial cells and by transient plasmid cDNA transfection in immortalized microvascular endothelial cells. Transcriptional profiling combined with quantitative real-time reverse transcription-polymerase chain reaction and Western blotting analyses have revealed that Prox1 expression up-regulates the lymphatic endothelial cell markers podoplanin and vascular endothelial growth factor receptor-3. Conversely, genes such as laminin, vascular endothelial growth factor-C, neuropilin-1, and intercellular adhesion molecule-1, whose expression has been associated with the blood vascular endothelial cell phenotype, are down-regulated. These findings validate the proposal that Prox1 is a key player in the molecular pathway leading to the formation of lymphatic vasculature and identify Prox1 as a master switch in the program specifying lymphatic endothelial cell fate. That a single gene product is sufficient to re-program the blood vascular endothelium toward a lymphatic phenotype corroborates the close relationship between these two vascular systems and also suggests that during evolution, the lymphatic vasculature originated from the blood vasculature by the additional expression of only a few gene products such as Prox1 (Hong, 2002).

Although important progress has been made recently in the elucidation of the molecular mechanisms that regulate differentiation and morphogenesis of endoderm-derived tissues such as pancreas and liver, less is known about the preliminary steps of early regional specification. Recent evidence supports the proposal that the early endoderm contains a bipotential precursor cell type for pancreas and liver. The activity of the homeobox gene Prox1 controls hepatocyte migration during liver morphogenesis. Using detailed comparative analysis of whole embryos and reverse transcriptase polymerase chain reaction of dissected embryonic endoderm, it has been determined that in the early endoderm Prox1 expression is restricted to regions giving rise to the mammalian pancreas and liver. This finding indicates that Prox1 is one of the earliest specific markers of this commonly fated region of the mammalian endoderm (Burke, 2002).

Prox1, the vertebrate cognate of Drosophila Prospero, is a homeodomain protein essential for the development of the lens, liver and lymphatic system. While it is well established that the subcellular distribution of Prospero changes during development, this had not been demonstrated for Prox1. High-resolution confocal microscopy has demonstrated that Prox1 protein is predominately cytoplasmic in the lens placode as well as the lens epithelium and germinative zone throughout development. However during fiber cell differentiation, Prox1 protein redistributes to cell nuclei. Finally, as lens fiber cells condense their chromatin in response to lens denucleation, Prox1 remains in the nucleus but does not appear to interact with DNA. Thus, it appears that the function of Prox1, like that of its Drosophila cognate Prospero, is at least partially controlled by changes in its subcellular distribution during development (Duncan, 2002).

Gamma-crystallin genes are specifically expressed in the eye lens. Their promoters constitute excellent models to analyse tissue-specific gene expression. Murine CRYGE/f promoters of different length have been investigated in lens epithelial cell lines. The most active fragment extends from position -219 to +37. Computer analysis predicts homeodomain and paired-domain binding sites for all rodent CRYGD/e/f core promoters. As examples, the effects of Prox1 and Six3, which are considered important transcription factors involved in lens development, were examined. Because of endogenous Prox1 expression in N/N1003A cells, a weak stimulation of CRYGE/f promoter activity was found for PROX1. In contrast, PROX1 stimulates the CRYGF promoter 10-fold in CD5A cells without endogenous PROX1. In both cell lines Six3 represses the CRYGF promoter to 10% of its basal activity. These cell transfection experiments indicate that CRYG expression increases as Six3 expression decreases. Prox1 and Six3 act antagonistically on regulation of the CRYGD/e/f promoters. Functional assays using randomly mutated gammaF-crystallin promoter fragments define a Six3-responsive element between -101 and -123 and a Prox1-responsive element between -151 and -174. Since Prox1 and Six3 are present at the beginning of lens development, expression of CRYGD/e/f is predicted to remain low at this time. It increases as Six3 expression decreases during ongoing lens development (Lengler, 2001).

Several genes are required during the early phases of liver specification, proliferation and differentiation. Prox1 is required for hepatocyte migration. Loss of Prox1 leads to formation of a smaller liver with a reduced population of clustered hepatocytes surrounded by a laminin-rich basal membrane (Sosa-Pineda, 2000).

prospero-related homeobox genes have been identified from various multi-cellular organisms and play important roles in development as a cell fate determinant. Mouse Prox1 is essential for embryogenesis and is required to differentiate horizontal cells in the retina. This study describes a novel prospero family member, Prox2. Transcriptional reporter assays demonstrated that mouse Prox2 is a transcriptional activator and the N-terminal region has been identified as an activation domain. The expression of mouse Prox2 was detected in postnatal eyes and adult testes as well as embryos. To investigate the in vivo role of Prox2, the Prox2 mutant allele, Prox2 -, was generated by homologous recombination in mouse ES cells. Prox2 - lacks the first coding exon that encodes a translational start site and a part of homeodomain. In spite of the Prox2 expression during embryogenesis, Prox2 - homozygous mutant mice are born at the expected Mendelian ratio without overt abnormalities. Histological analyses revealed that Prox2 - homozygous eyes retained the organized layer structure including three nuclear layers and differentiated horizontal cells. Prox2 - homozygous mutant males produced elongated spermatids and were fertile. These results demonstrate that mouse Prox2 is dispensable for embryonic development, horizontal cell generation and fertility in contrast to mouse Prox1 (Nishijima, 2006).

Prox1 and lymphatic development

During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. This study identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, expression of HoxD8 was found to be significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. It was also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, HoxD8 induces Prox1 expression in HUVECs and knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels (Harada, 2009).

The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells

The homeobox gene Prox1 is crucial for mammalian lymphatic vascular development. In the absence of Prox1, lymphatic endothelial cells (LECs) are not specified. The maintenance of LEC identity also requires the constant expression of Prox1. However, the mechanisms controlling the expression of this gene in LECs remain poorly understood. The SRY-related gene Sox18 is required to induce Prox1 expression in venous LEC progenitors. Although Sox18 is also expressed in embryonic arteries, these vessels do not express Prox1, nor do they give rise to LECs. This finding suggests that some venous endothelial cell-specific factor is required for the activation of Prox1. This study demonstrates that the nuclear hormone receptor Coup-TFII is necessary for the activation of Prox1 in embryonic veins by directly binding a conserved DNA domain in the regulatory region of Prox1. In addition, it was shown that the direct interaction between nuclear hormone receptors and Prox1 is also necessary for the maintenance of Prox1 expression during early stages of LEC specification and differentiation (Srinivasan, 2010).

The homeobox protein Prox1 is a negative modulator of ERRα/PGC-1α bioenergetic functions

Estrogen-related receptor α (ERRα) and proliferator-activated receptor γ coactivator-1α (PGC-1α) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. This study identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRα and PGC-1α, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERRα/PGC-1α complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERRα and other factors. Importantly, ablation of Prox1 and ERRα have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis (Charest-Marcotte, 2010).

Prospero homologs and neural development

The expression patterns of the homeobox genes Pax-6, Prox 1, and Chx10 were examined during chick retinal development in vivo and in vitro. Until embryonic day (ED) 5, in situ hybridization shows widespread, diffuse distribution of all three genes. Between ED 6 and ED 8, however, they acquire distinct, topographically specific patterns of expression. The Prox 1 signal is predominantly expressed in the prospective horizontal cell layer of the neuroepithelium, decreases vitreally, and is absent from ganglion cells and the prospective photoreceptor layer. Pax-6 is strongly expressed only in the prospective ganglion-cell and amacrine-cell regions at the same stages, and is not detected in prospective photoreceptors. Chx10 expression becomes concentrated in the future bipolar-cell region of the inner nuclear layer. Similar patterns are maintained by ED 15 through ED 18, after cell differentiation has taken place. Pax-6 and Prox 1 immunoreactive materials show nuclear localization and a pattern of laminar distribution equivalent to that seen by in situ hybridization. These results suggest that the differentiated fate of retinal precursor cells may be influenced by Pax-6, Prox 1, or Chx10. This hypothesis is now being tested using dissociated chick embryo retinal cell cultures (Belecky-Adams, 1997).

Like other tissues and organs in vertebrates, multipotential stem cells serve as the origin of diverse cell types during genesis of the mammalian central nervous system (CNS). During early development, stem cells self-renew and increase their total cell numbers without overt differentiation. At later stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step in cell differentiation remain poorly understood. In this study, evidence is presented that the expression and function of the neural-specific transcription factors Mash-1 and Prox-1, related to Drosophila Prospero, are involved in this process. In the developing rat forebrain and E13.5, the Mash-1+ domain covers the ventral thalamus, hypothalamus and ganglionic eminence. Strong expression is also seen in the dorsal midbrain, where neurogenesis proceeds earlier than in the forebrain. In contrast, the dorsal thalamus and the primordia of the cerebral cortex are devoid of expression of Mash-1 at this stage. Prox-1 follows the discrete patterns of Mash-1, which also demarcates sharp boundaries. These characteristic expression patterns are reminiscent of the two brain-specific homeobox genes, Dlx-1 and Pax-6. In vivo, Mash-1- and Prox-1-expressing cells are defined as a transient proliferating population that is molecularly distinct from self-renewing stem cells. By taking advantage of in vitro culture systems, induction of Mash-1 and Prox-1 has been shown to coincide with an initial step of stem cell differentiation. Furthermore, forced expression of Mash-1 leads to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and up-regulation of Prox-1, suggesting that Mash-1 positively regulates cell differentiation. In support of these observations in vitro, specific defects are found in cellular differentiation and loss of expression of Prox-1 in the developing brain of Mash-1 mutant mice in vivo. Thus, it is proposed that induction of Mash-1 and Prox-1 is one of the critical molecular events that control early development of the CNS (Torri, 1999).

Retinal progenitor cells regulate their proliferation during development so that the correct number of each cell type is made at the appropriate time. The homeodomain protein Prox1 regulates the exit of progenitor cells from the cell cycle in the embryonic mouse retina. Cells lacking Prox1 are less likely to stop dividing, and ectopic expression of Prox1 forces progenitor cells to exit the cell cycle. During retinogenesis, Prox1 can be detected in differentiating horizontal, bipolar and AII amacrine cells. Horizontal cells are absent in retinae of Prox1-/- mice and misexpression of Prox1 in postnatal progenitor cells promotes horizontal-cell formation. Thus, Prox1 activity is both necessary and sufficient for progenitor-cell proliferation and cell-fate determination in the vertebrate retina (Dyer, 2003).

During vertebrate retinogenesis, seven classes of cells are specified from multipotent progenitors. To date, the mechanisms underlying multipotent cell fate determination by retinal progenitors remain poorly understood. The Foxn4 winged helix/forkhead transcription factor is shown to be expressed in a subset of mitotic progenitors during mouse retinogenesis. Targeted disruption of Foxn4 largely eliminates amacrine neurons and completely abolishes horizontal cells, while overexpression of Foxn4 strongly promotes an amacrine cell fate. These results indicate that Foxn4 is both necessary and sufficient for commitment to the amacrine cell fate and is nonredundantly required for the genesis of horizontal cells. Furthermore, evidence is provided that Foxn4 controls the formation of amacrine and horizontal cells by activating the expression of the retinogenic factors Math3, NeuroD1, and the Prospero-like transcription factor Prox1. These data suggest a model in which Foxn4 cooperates with other key retinogenic factors to mediate the multipotent differentiation of retinal progenitors (Li, 2004).

PROX1: a lineage tracer for cortical interneurons originating in the lateral/caudal ganglionic eminence and preoptic area

The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, it was demonstrated that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons. These correspond to interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) and a small number of preoptic area (POA)-derived neurons. Expression within the cortex can be detected from late embryonic stages onwards when cortical interneurons are still migrating. There is persistent expression in postmitotic cells in the mature brain mainly in the outer cortical layers. PROX1(+ve) interneurons express neurochemical markers such as calretinin, neuropeptide Y, reelin and vasoactive intestinal peptide, all of which are enriched in LGE/CGE- and some POA-derived cells. Unlike in the cortex, in the striatum PROX1 marks nearly all interneurons regardless of their origin. Weak expression of PROX1 can also be detected in oligodendrocyte lineage cells throughout the forebrain. These data show that PROX1 can be used as a genetic lineage tracer of nearly all LGE/CGE- and subsets POA-derived cortical interneurons at all developmental and postnatal stages in vivo (Rubin, 2013).

PROS-1/Prospero is a major regulator of the glia-specific secretome controlling sensory-neuron shape and function in C. elegans

Sensory neurons are an animal's gateway to the world, and their receptive endings, the sites of sensory signal transduction, are often associated with glia. Although glia are known to promote sensory-neuron functions, the molecular bases of these interactions are poorly explored. This study describes a post-developmental glial role for the PROS-1/Prospero/PROX1 homeodomain protein in sensory-neuron function in C. elegans. Using glia expression profiling, it was demonstrated that, unlike previously characterized cell fate roles, PROS-1 functions post-embryonically to control sense-organ glia-specific secretome expression. PROS-1 functions cell autonomously to regulate glial secretion and membrane structure, and non-cell autonomously to control the shape and function of the receptive endings of sensory neurons. Known glial genes controlling sensory-neuron function are PROS-1 targets, and this study identified additional PROS-1-dependent genes required for neuron attributes. Drosophila Prospero and vertebrate PROX1 are expressed in post-mitotic sense-organ glia and astrocytes, suggesting conserved roles for this class of transcription factors (Wallace, 2016).

Caenorhabditis elegans homologue of Prox1/Prospero is expressed in the glia and is required for sensory behavior and cold tolerance

The Caenorhabditis elegans (C. elegans) amphid sensory organ contains only 4 glia-like cells and 24 sensory neurons, providing a simple model for analyzing glia or neuron-glia interactions. To better characterize glial development and function, RNA interference screening was carried out for transcription factors that regulate the expression of an amphid sheath glial cell marker. pros-1, which encodes a homeodomain transcription factor homologous to Drosophila Prospero/mammalian Prox1, was identified as a positive regulator. The functional PROS-1::EGFP fusion protein was localized in the nuclei of the glia and the excretory cell but not in the amphid sensory neurons. pros-1, deletion mutants exhibited larval lethality, and rescue experiments showed that pros-1, and human Prox1 transgenes were able to rescue the larval lethal phenotype, suggesting that pros-1, is a functional homologue of mammalian Prox1, at least partially. It was further found that the structure and functions of sensory neurons, such as the morphology of sensory endings, sensory behavior and sensory-mediated cold tolerance, appeared to be affected by the pros-1, RNAi. Together, these results show that the C. elegans PROS-1 is a transcriptional regulator in the glia but is involved not only in sensory behavior but also in sensory-mediated physiological tolerance (Kage-Nakadai, 2016).

Prox1 maintains muscle structure and growth in the developing heart

Impaired cardiac muscle growth and aberrant myocyte arrangement underlie congenital heart disease and cardiomyopathy. Cardiac-specific inactivation of the murine homeobox transcription factor Prox1 results in the disruption of expression and localisation of sarcomeric proteins, gross myofibril disarray and growth-retarded hearts. Furthermore, Prox1 is shown to be required for direct transcriptional regulation of the genes encoding the structural proteins alpha-actinin, N-RAP and zyxin, which collectively function to maintain an actin-alpha-actinin interaction as the fundamental association of the sarcomere. Aspects of abnormal heart development and the manifestation of a subset of muscular-based disease have previously been attributed to mutations in key structural proteins. This study reveals an essential requirement for direct transcriptional regulation of sarcomere integrity, in the context of enabling foetal cardiomyocyte hypertrophy, maintenance of contractile function and progression towards inherited or acquired myopathic disease (Risebro, 2009).

Biological Overview | Regulation | Protein Interactions | Developmental Biology | Effects of Mutation | References

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