Utility of special AT-rich sequence-binding protein 2 (SATB2) immunohistochemistry as a marker for secondary perianal paget disease.

A panel-based approach using immunohistochemistry (IHC) is currently used for subtyping perianal Paget disease (PPD) in the absence of a synchronous neoplasm. Special AT-rich Sequence Binding Protein 2 (SATB2) has been established as a sensitive and specific marker for lower gastrointestinal tract carcinomas. We evaluated its performance as a marker of secondary PPD. A panel of IHCs including CK7, CK20, GCDFP-15, CDX2, and SATB2 were performed on fifteen cases of PPD (identified between 1991-2001) and seven cases of primary vulvar Paget disease with perianal involvement. Eight cases (53%) were classified as secondary PPD based on the presence of a synchronous (n = 7) or a metachronous neoplasm (n = 1). There was no differential staining for CK7 (positive in 7/7 primary vs. 7/8 secondary PPD; P = 1.00) and CK20 (positive in 4/7 primary vs. 8/8 secondary PPD; P = .08). GCDFP-15 was positive in 5/7 cases of primary PPD while negative in all cases of secondary PPD (P = .01). CDX2 was positive in all cases of secondary PPD (P = .001) while SATB2 was positive in 7/8 cases of secondary PPD (P = .01). Both CDX2 and SATB2 were positive in 1/7 cases of primary PPD. The addition of an IHC panel in conjunction with clinical/imaging findings can help definitively classify PPD as either primary or secondary in most cases. We show that SATB2 has comparable performance to CDX2 and can be a helpful additional tool.

Region-specific gene expression profiling of early mouse mandible uncovered SATB2 as a key molecule for teeth patterning.

Mammalian dentition exhibits distinct heterodonty, with more simple teeth located in the anterior area of the jaw and more complex teeth situated posteriorly. While some region-specific differences in signalling have been described previously, here we performed a comprehensive analysis of gene expression at the early stages of odontogenesis to obtain complete knowledge of the signalling pathways involved in early jaw patterning. Gene expression was analysed separately on anterior and posterior areas of the lower jaw at two early stages (E11.5 and E12.5) of odontogenesis. Gene expression profiling revealed distinct region-specific expression patterns in mouse mandibles, including several known BMP and FGF signalling members and we also identified several new molecules exhibiting significant differences in expression along the anterior-posterior axis, which potentially can play the role during incisor and molar specification. Next, we followed one of the anterior molecules, SATB2, which was expressed not only in the anterior mesenchyme where incisor germs are initiated, however, we uncovered a distinct SATB2-positive region in the mesenchyme closely surrounding molars. Satb2-deficient animals demonstrated defective incisor development confirming a crucial role of SATB2 in formation of anterior teeth. On the other hand, ectopic tooth germs were observed in the molar area indicating differential effect of Satb2-deficiency in individual jaw regions. In conclusion, our data provide a rich source of fundamental information, which can be used to determine molecular regulation driving early embryonic jaw patterning and serve for a deeper understanding of molecular signalling directed towards incisor and molar development.

SATB1 and p16 Expression and Prognostic Value in Croatian Hodgkin Lymphoma Patients: A Unicentric Study.

Hodgkin lymphoma (HL) is a rare lymphoid neoplasm in which Hodgkin/Reed-Stenberg (HRS) cells are admixed with a population of non-neoplastic inflammatory cells and fibrosis. Dysregulated expressions of cell cycle regulators and transcription factors have been proven as one of the hallmarks of HL. In that context, SATB1 and p16 have been reported as potential regulators of HL progression and survival. However, to date, no studies have assessed the expression levels of SATB1 and p16 in HL in Croatian patients or their prognostic values. Therefore, we investigated the expression pattern of SATB1 and p16 in paraffin-embedded lymph node biopsies using standard immunohistochemistry. We found that 21% of the patients stained positive for SATB1, while 15% of the patients displayed positive staining for p16. Furthermore, we aimed to understand the prognostic value of each protein through the analysis of the overall survival (OS) and progression-free survival (PFS). SATB1 showed a significantly positive correlation with better OS and PFS, while p16 expression had no impact. Interestingly, when patients were stratified by a combination of the two studied markers, we found that patients in the SATB1+/p16- group tended to have the best prognosis in HL, according to statistical significance. In conclusion, SATB1 and p16 might be potentially useful as diagnostic and prognostic markers for HL.

Spatial transcriptome reveals the region-specific genes and pathways regulated by Satb2 in neocortical development.

BACKGROUND: It is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development. RESULTS: In this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2+/+ and Satb2-/- mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2-/- mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2-/- mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2-/- mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2-/- mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2-/- mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR. CONCLUSIONS: In summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.

Glass syndrome derived from chromosomal breakage downstream region of SATB2.

BACKGROUND: Glass syndrome, derived from chromosomal 2q33.1 microdeletions, manifests with intellectual disability, microcephaly, epilepsy, and distinctive features, including micrognathia, down-slanting palpebral fissures, cleft palate, and crowded teeth. Recently, SATB2 located within the deletion region, was identified as the causative gene responsible for Glass syndrome. Numerous disease-causing variants within the SATB2 coding region have been reported. OBJECTIVE: Given the presentation of intellectual disability and multiple congenital anomalies in a patient with a de novo reciprocal translocation between chromosomes 1 and 2, disruption of the causative gene(s) was suspected. This study sought to identify the causative gene in the patient. METHODS: Long-read whole-genome sequencing was performed, and the expression level of the candidate gene was analyzed. RESULTS: The detection of breakpoints was successful. While the breakpoint on chromosome 1 disrupted RNF220, it was not deemed to be a genetic cause. Conversely, SATB2 is located in the approximately 100-kb telomeric region of the breakpoint on chromosome 2. The patient's clinical features resembled those of previously reported cases of Glass syndrome, despite the lack of confirmed reduced SATB2 expression. CONCLUSION: The patient was diagnosed with Glass syndrome due to the similarity in clinical features. This led us to hypothesize that disruption in the downstream region of SATB2 could result in Glass syndrome. The microhomologies identified in the breakpoint junctions indicate a potential molecular mechanism involving microhomology-mediated break-induced repair mechanism or template switching.

Immunohistochemical expression of SATB2 and PAX8 in differentiating primary from metastatic ovarian mucinous neoplasms.

Accurate stratification of an ovarian mucinous neoplasm as primary or secondary is always challenging as they show overlapping histomorphological and immunohistochemical features. Immunohistochemical staining for SATB2 and PAX8 was performed on 80 cases of mucinous ovarian neoplasms subdivided into 53 primary [25 primary ovarian mucinous carcinomas (POMCs) and 28 mucinous borderline tumors (MBTs)] and 27 secondary (12 of colonic origin, 7 of appendiceal origin, and 8 of gastric origin). Expression was correlated with different clinicopathologic parameters. PAX8-positive immunostaining was detected in 38 out of 53 cases (71.69%) of primary ovarian mucinous neoplasms (POMNs) with null positivity in the secondary ovarian mucinous tumors (0/27). SATB2-positive expression was detected in 16 out of 27 cases (59.26%) of the secondary ovarian mucinous tumors. None of the studied POMNs showed any positive immunostaining for SATB2 (0/53). A profile of SATB2-/PAX8+ and SATB2+/PAX8- can be used to differentiate POMNCs from secondary ovarian mucinous tumors of GI origin, respectively, with 100% specificity. PAX8 expression is associated with some clinicopathologic parameters providing the basis for the possible usage of PAX8 as prognostic marker.

Telangiectatic osteosarcoma of the mandible-A rare case report and an insight into differential diagnosis.

Telangiectatic osteosarcoma (TOS) is a rare variant of osteosarcoma that typically affects young individuals and long bones. The case under discussion was seen in the mandible of a 57-year-old female and had rapidly grown in size within a week. Microscopically, the tumour was characterised by large vascular cavities surrounded by anaplastic cells. Thin lacy tumour osteoid was observed at various foci. Abundant multinucleated osteoclastic giant cells along with areas of necrosis were also noted. The tumour cells were positive for SATB2, while negative for Cytokeratin AE1/3, CD 34. Ki-67 positivity was observed in more than 50% of tumour cells. A diagnosis of high grade telangiectatic osteosarcoma was thus made.

HucMSC extracellular vesicles increasing SATB 1 to activate the Wnt/ß-catenin pathway in 6-OHDA-induced Parkinson's disease model.

Parkinson's disease (PD) is a degenerative disorder of the nervous system characterized by the loss of dopaminergic neurons and damage of neurons in the substantia nigra (SN) and striatum, resulting in impaired motor functions. This study aims to investigate how extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HucMSC) regulate Special AT-rich sequence-binding protein-1 (SATB 1) and influence Wnt/ß-catenin pathway and autophagy in PD model. The PD model was induced by damaging SH-SY5Y cells and mice using 6-OHDA. According to the study, administering EVs every other day for 14 days improved the motor behavior of 6-OHDA-induced PD mice and reduced neuronal damage, including dopaminergic neurons. Treatment with EVs for 12 hours increased the viability of 6-OHDA-induced SH-SY5Y cells. The upregulation of SATB 1 expression with EV treatment resulted in the activation of the Wnt/ß-catenin pathway in PD model and led to overexpression of ß-catenin. Meanwhile, the expression of LC3 II was decreased, indicating alterations in autophagy. In conclusion, EVs could mitigate neuronal damage in the 6-OHDA-induced PD model by upregulating SATB 1 and activating Wnt/ß-catenin pathway while also regulating autophagy. Further studies on the potential therapeutic applications of EVs for PD could offer new insights and strategies.

PCSK2 can be Useful in a Panel Approach to Distinguish Foregut and Midgut Neuroendocrine Tumors.

A number of immunohistochemical stains have been examined for utility in establishing the site of origin for metastatic well-differentiated neuroendocrine tumors (NETs). In the gastrointestinal (GI) tract, distinguishing metastatic duodenal NETs from jejunoileal and other GI NETs is important for clinical work-up, prognosis, and therapy. A recent study indicated that prohormone convertase 2 (PCSK2 or PC2) had broad expression in small intestine and appendiceal NETs. Because the study did not include duodenal NETs, we examined PCSK2 expression in duodenal and other GI NETs.GI NETs (n = 69) and 13 corresponding lymph node metastases from stomach, duodenum, pancreas, ileum, appendix, and rectum were evaluated for the expression of PCSK2, along with ISL1, NKX2.2, CDX2, SATB2, and PAX8. Expression of each stain was evaluated using the H-score system, and differences in expression by site were evaluated by the chi square test.PCSK2 was expressed at similar frequency in duodenal (50%), pancreatic (59%), and ileal NETs (40%). PCSK2 was infrequently expressed in stomach (0%), appendiceal (8%), and rectal (25%) NETs. However, incorporating PCSK2 into a panel including ISL1, NKX2.2, CDX2, and SATB2 allowed development of an algorithm which had 87% sensitivity and 93% specificity for classification of ileal NETs; and 68% sensitivity and 98% specificity for pancreaticoduodenal NETs.In contrast to previous findings, PCSK2 does not show specificity for any particular GI site. An algorithmic approach incorporating the expression of PCSK2 with that of ISL1, NKX2.2, CDX2, and SATB2 is useful in discriminating pancreatic, duodenal, ileal, appendiceal, and rectal NETs.

The utility of the lineage specific immunohistochemical stains SATB2, CDX2, and villin, and the mucin glycoproteins MUC2, MUC5AC, and MUC6 to distinguish pulmonary invasive mucinous adenocarcinoma from metastatic colorectal carcinoma.

CONTEXT: The lungs are a common site of tumor metastasis. While morphology and immunophenotype can help differentiate primary from metastatic tumors, distinguishing pulmonary invasive mucinous adenocarcinoma (PIMA) from metastatic colorectal adenocarcinoma (CRC) may occasionally be challenging due to overlapping morphological and immunohistochemical features. Lineage-specific markers such as CDX2, TTF-1, and napsin A are helpful with pulmonary non-mucinous adenocarcinoma (PNMA), however they are non-specific and insensitive when applied to PIMA. SATB2 is a newer marker that distinguishes CRC from upper gastrointestinal and pancreaticobiliary tumors; its utility in distinguishing CRC from PIMA has not been fully elucidated. OBJECTIVE: To evaluate the performance of lineage-specific and mucin glycoprotein immunostains in distinguishing PIMA and CRC. DESIGN: We stained tissue microarrays comprising 34 PNMA, 31 PIMA, and 32 CRC with CK7, CK20, SATB2, CDX2, villin, TTF-1, napsin A, and gel-forming mucins MUC2, MUC5AC, and MUC6. RESULTS: PIMA showed significant (>50% of cells) expression of SATB2 (6%), CDX2 (6%), villin (74%), TTF-1 (13%), and napsin A (23%). However, significant CK7 expression was seen in nearly all PIMA (30/31) and none of the metastatic CRC. CONCLUSION: Our results suggest that CK7 remains one of the most useful markers for distinguishing primary PIMA from metastatic CRC. Expression of the mucin glycoproteins MUC5AC and MUC6 and lack of expression of MUC2 favored a diagnosis of PIMA, but expression of these markers was too heterogeneous to be of clinical utility. To our knowledge this is the only study comparing the immunohistochemical profile of PIMA and metastatic CRC in lung metastasectomy specimens.

The Clinicopathological Significance of Tumor Cell Subtyping in Appendiceal Neuroendocrine Tumors: A Series of 135 Tumors.

Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior.

Oncogenic Role of SATB2 In Vitro: Regulator of Pluripotency, Self-Renewal, and Epithelial-Mesenchymal Transition in Prostate Cancer.

Special AT-rich sequence binding protein-2 (SATB2) is a nuclear matrix protein that binds to nuclear attachment regions and is involved in chromatin remodeling and transcription regulation. In stem cells, it regulates the expression of genes required for maintaining pluripotency and self-renewal and epithelial-mesenchymal transition (EMT). In this study, we examined the oncogenic role of SATB2 in prostate cancer and assessed whether overexpression of SATB2 in human normal prostate epithelial cells (PrECs) induces properties of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in prostate cancer cell lines and CSCs, but not in PrECs. Overexpression of SATB2 in PrECs induces cellular transformation which was evident by the formation of colonies in soft agar and spheroids in suspension. Overexpression of SATB2 in PrECs also resulted in induction of stem cell markers (CD44 and CD133), pluripotency-maintaining transcription factors (cMYC, OCT4, SOX2, KLF4, and NANOG), CADHERIN switch, and EMT-related transcription factors. Chromatin immunoprecipitation assay demonstrated that SATB2 can directly bind to promoters of BCL-2, BSP, NANOG, MYC, XIAP, KLF4, and HOXA2, suggesting SATB2 is capable of directly regulating pluripotency/self-renewal, cell survival, and proliferation. Since prostate CSCs play a crucial role in cancer initiation, progression, and metastasis, we also examined the effects of SATB2 knockdown on stemness. SATB2 knockdown in prostate CSCs inhibited spheroid formation, cell viability, colony formation, cell motility, migration, and invasion compared to their scrambled control groups. SATB2 knockdown in CSCs also upregulated the expression of E-CADHERIN and inhibited the expression of N-CADHERIN, SNAIL, SLUG, and ZEB1. The expression of SATB2 was significantly higher in prostate adenocarcinoma compared to normal tissues. Overall, our data suggest that SATB2 acts as an oncogenic factor where it is capable of inducing malignant changes in PrECs by inducing CSC characteristics.

The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

SATB1, senescence and senescence-related diseases.

Aging leads to an accumulation of cellular mutations and damage, increasing the risk of senescence, apoptosis, and malignant transformation. Cellular senescence, which is pivotal in aging, acts as both a guard against cellular transformation and as a check against cancer progression. It is marked by stable cell cycle arrest, widespread macromolecular changes, a pro-inflammatory profile, and altered gene expression. However, it remains to be determined whether these differing subsets of senescent cells result from unique intrinsic programs or are influenced by their environmental contexts. Multiple transcription regulators and chromatin modifiers contribute to these alterations. Special AT-rich sequence-binding protein 1 (SATB1) stands out as a crucial regulator in this process, orchestrating gene expression by structuring chromatin into loop domains and anchoring DNA elements. This review provides an overview of cellular senescence and delves into the role of SATB1 in senescence-related diseases. It highlights SATB1's potential in developing antiaging and anticancer strategies, potentially contributing to improved quality of life and addressing aging-related diseases.

Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome.

SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.

ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum.

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.

Non-Specific Epileptic Activity, EEG, and Brain Imaging in Loss of Function Variants in SATB1: A New Case Report and Review of the Literature.

SATB1 (MIM #602075) is a relatively new gene reported only in recent years in association with neurodevelopmental disorders characterized by variable facial dysmorphisms, global developmental delay, poor or absent speech, altered electroencephalogram (EEG), and brain abnormalities on imaging. To date about thirty variants in forty-four patients/children have been described, with a heterogeneous spectrum of clinical manifestations. In the present study, we describe a new patient affected by mild intellectual disability, speech disorder, and non-specific abnormalities on EEG and neuroimaging. Family studies identified a new de novo frameshift variant c.1818delG (p.(Gln606Hisfs*101)) in SATB1. To better define genotype-phenotype associations in the different types of reported SATB1 variants, we reviewed clinical data from our patient and from the literature and compared manifestations (epileptic activity, EEG abnormalities and abnormal brain imaging) due to missense variants versus those attributable to loss-of-function/premature termination variants. Our analyses showed that the latter variants are associated with less severe, non-specific clinical features when compared with the more severe phenotypes due to missense variants. These findings provide new insights into SATB1-related disorders.

Meta-analysis of SATB2 immunohistochemical expression in colorectal cancer versus primary ovarian mucinous neoplasms.

BACKGROUND: Reliably distinguishing primary ovarian mucinous neoplasms (POMNs) from metastatic colorectal cancers (CRCs) is both challenging to the histopathologist and of great clinical importance. Special AT-rich sequence binding protein-2 (SATB2) has emerged as a useful diagnostic immunohistochemical marker of colorectal cancer. This meta-analysis compares SATB2 expression in POMNs and CRC. METHODS: A systematic literature search for relevant studies was conducted. Meta-analysis of SATB2 positivity was undertaken using a random effects model. RESULTS: Seven studies including 711 CRCs and 528 POMNs were included. SATB2 positivity was seen in 81 % (95 % CI: 72-88 %) of CRCs and 4 % (95 % CI: 1-11 %) of POMNs. Variation was seen in immunohistochemical methods used for SATB2 detection and threshold for positivity. CONCLUSION: SATB2 staining remains high in CRC and low in POMNs, supporting its use in differentiating these two pathologies with vastly differing prognosis and treatment.

Genetic mechanism regulating diversity in the placement of eyes on the head of animals.

Despite the conservation of genetic machinery involved in eye development, there is a strong diversity in the placement of eyes on the head of animals. Morphogen gradients of signaling molecules are vital to patterning cues. During Drosophila eye development, Wingless (Wg), a ligand of Wnt/Wg signaling, is expressed anterolaterally to form a morphogen gradient to determine the eye- versus head-specific cell fate. The underlying mechanisms that regulate this process are yet to be fully understood. We characterized defective proventriculus (dve) (Drosophila ortholog of human SATB1), a K50 homeodomain transcription factor, as a dorsal eye gene, which regulates Wg signaling to determine eye versus head fate. Across Drosophila species, Dve is expressed in the dorsal head vertex region where it regulates wg transcription. Second, Dve suppresses eye fate by down-regulating retinal determination genes. Third, the dve-expressing dorsal head vertex region is important for Wg-mediated inhibition of retinal cell fate, as eliminating the Dve-expressing cells or preventing Wg transport from these dve-expressing cells leads to a dramatic expansion of the eye field. Together, these findings suggest that Dve regulates Wg expression in the dorsal head vertex, which is critical for determining eye versus head fate. Gain-of-function of SATB1 exhibits an eye fate suppression phenotype similar to Dve. Our data demonstrate a conserved role for Dve/SATB1 in the positioning of eyes on the head and the interocular distance by regulating Wg. This study provides evidence that dysregulation of the Wg morphogen gradient results in developmental defects such as hypertelorism in humans where disproportionate interocular distance and facial anomalies are reported.