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Disease Models & Mechanisms May 2012Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly...
Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ~10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.
Topics: Abnormalities, Multiple; Animals; Anus, Imperforate; Body Patterning; Cell Count; Cell Cycle; Cell Differentiation; Cell Lineage; Cerebral Cortex; Gene Deletion; Hearing Loss, Sensorineural; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neurogenesis; Neuroglia; Organ Size; Stem Cells; Thumb; Transcription Factors
PubMed: 22228756
DOI: 10.1242/dmm.002873 -
Indian Pediatrics Feb 2007Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies,...
Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, limb deformity, imperforate anus, and renal malformations. Hypothyroidism is not a recognized feature of TBS. We are reporting a case of TBS with hypothyroidism, a rare association.
Topics: Abnormalities, Multiple; Anus, Imperforate; Child, Preschool; Ear, External; Female; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Kidney; Syndrome
PubMed: 17351307
DOI: No ID Found -
The Journal of Biological Chemistry Jan 2011Sall1 is a multi-zinc finger transcription factor that regulates kidney organogenesis. It is considered to be a transcriptional repressor, preferentially localized on...
Sall1 is a multi-zinc finger transcription factor that regulates kidney organogenesis. It is considered to be a transcriptional repressor, preferentially localized on heterochromatin. Mutations or deletions of the human SALL1 gene are associated with the Townes-Brocks syndrome. Despite its high expression, no function was yet assigned for Sall1 in embryonic stem (ES) cells. In the present study, we show that Sall1 is expressed in a differentiation-dependent manner and physically interacts with Nanog and Sox2, two components of the core pluripotency network. Genome-wide mapping of Sall1-binding loci has identified 591 genes, 80% of which are also targeted by Nanog. A large proportion of these genes are related to self-renewal and differentiation. Sall1 positively regulates and synergizes with Nanog for gene transcriptional regulation. In addition, our data show that Sall1 suppresses the ectodermal and mesodermal differentiation. Specifically, the induction of the gastrulation markers T brachyury, Goosecoid, and Dkk1 and the neuroectodermal markers Otx2 and Hand1 was inhibited by Sall1 overexpression during embryoid body differentiation. These data demonstrate a novel role for Sall1 as a member of the transcriptional network that regulates stem cell pluripotency.
Topics: Cell Differentiation; Chromatin; Embryonic Stem Cells; Gene Expression Regulation, Developmental; HEK293 Cells; Homeodomain Proteins; Humans; Nanog Homeobox Protein; Oligonucleotide Array Sequence Analysis; Pluripotent Stem Cells; SOXB1 Transcription Factors; Transcription Factors; Transcription, Genetic
PubMed: 21062744
DOI: 10.1074/jbc.M110.170050 -
American Journal of Human Genetics Feb 1999Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that...
Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.
Topics: Abnormalities, Multiple; Anus, Imperforate; Base Sequence; Cloning, Molecular; Exons; Female; Frameshift Mutation; Hearing Loss, Sensorineural; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Polymorphism, Genetic; Syndrome; Transcription Factors; Zinc Fingers
PubMed: 9973281
DOI: 10.1086/302238 -
Nephron. Experimental Nephrology 2011Sall1 is a transcription factor that best identifies stem cells present in the mouse embryonic kidney. Mutations in Sall1 gene in mice can lead to dysgenesis of kidney,...
BACKGROUND
Sall1 is a transcription factor that best identifies stem cells present in the mouse embryonic kidney. Mutations in Sall1 gene in mice can lead to dysgenesis of kidney, while in humans it results in the Townes-Brocks syndrome, which is associated with the kidney agenesis. Unlike the embryonic kidney, Sall1 expression in the adult kidney is largely unknown. We hypothesized that similar to the embryonic kidney, Sall1 expression can identify stem cells present in the adult kidney. Accordingly in this study, we identified Sall1-expressing cells in the adult mouse kidney, determined their role in kidney regeneration following ischemia-reperfusion injury (IRI), and sought the effect of age on Sall1 expression.
METHODS AND RESULTS
By immunofluorescence Sall1-expressing cells were identified in the proximal tubule at the cortico-medullary junction and constituted 0.5% of all tubular cells. Rare Sall1-positive cells were also identified in the outer cortex and distal tubules. Sall1 expression was not seen in the glomerular, interstitial, or vascular compartments. Following IRI, 90% of Sall1-expressing cells proliferated and 5% of Sall1-positive cells showed asymmetrical cell division with one of the two adjacent Sall1-positive cells incorporating chlorodeoxyuridine (CldU). Following IRI, there was an increase in Sall1 expression at 4 and 12 h, a decrease at 5 and 10 days, and baseline expression at day 30 by quantitative polymerase chain reaction (qRT-PCR) and Western blot analysis. There was no age-related change in Sall1 expression as determined by qRT-PCR, Western blot analysis, and immunofluorescence.
CONCLUSIONS
We conclude that Sall1-expressing cells are present in the adult mouse kidney, predominantly in the proximal tubules. Sall1-expressing cells proliferate following IRI and some of the Sall1-positive cells undergo asymmetrical cell division. Therefore, Sall1 is a promising marker for identification of stem cells present in the adult mouse kidney.
Topics: Animals; Cell Division; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Regeneration; Reperfusion Injury; Tissue Distribution; Transcription Factors
PubMed: 21934330
DOI: 10.1159/000328925 -
Biochimica Et Biophysica Acta Mar 2006SALL1 has been identified as one of four human homologues of the Drosophila region-specific homeotic gene spalt (sal), encoding zinc finger proteins of characteristic...
SALL1 has been identified as one of four human homologues of the Drosophila region-specific homeotic gene spalt (sal), encoding zinc finger proteins of characteristic structure. Mutations of SALL1 on chromosome 16q12.1 cause Townes-Brocks syndrome (TBS, OMIM 107480). We have shown previously that SALL1 acts as a strong transcriptional repressor in mammalian cells when fused to a heterologous DNA-binding domain. Here, we report that SALL1 contains two repression domains, one located at the extreme N-terminus of the protein and the other in the central region. SALL1 fragments with the central repression domain exhibited a punctate nuclear distribution pattern at pericentromeric heterochromatin foci in murine NIH-3T3 cells, suggesting an association between repression and heterochromatin localization. The implications of these findings for the pathogenesis of Townes-Brocks syndrome are discussed.
Topics: Animals; Cell Nucleus; Chromosomes, Human, Pair 16; Genes, Reporter; Heterochromatin; Humans; Mice; Mutation; NIH 3T3 Cells; Protein Structure, Tertiary; Repressor Proteins; Syndrome; Transcription Factors; Transcription, Genetic; Zinc Fingers
PubMed: 16443351
DOI: 10.1016/j.bbadis.2005.12.005 -
European Journal of Pediatrics Apr 2016The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients... (Comparative Study)
Comparative Study
UNLABELLED
The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n = 12) and hypoplastic thumb (n = 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder-nine also met the VACTERL criteria-vs. 9 % of ARM patients with other anomalies (p = 0.004, chi-squared test).
CONCLUSION
Genetic disorders are twice as frequently diagnosed in ARM patients with upper limb anomalies than in those with other anomalies. As they also frequently meet the VACTERL criteria, it is important to consider VACTERL as a diagnosis per exclusionem. Genetic counseling is certainly warranted in these patients.
WHAT IS KNOWN
• Anorectal malformations (ARMs) often co-occur with other congenital anomalies, including upper limb anomalies, mainly of pre-axial origin. • Co-occurrence of ARMs and upper limb anomalies is seen in disorders such as Townes-Brocks syndrome, Fanconi anemia, and VACTERL association. What is New: • ARM patients with a major upper limb anomaly-with or without other congenital anomalies-have a twofold greater chance of a genetic disorder than have non-isolated ARM patients without upper limb anomalies. • Not all upper limb anomalies in ARM patients are part of the VACTERL association; a workup for genetic evaluation is proposed.
Topics: Anal Canal; Anorectal Malformations; Esophagus; Female; Genetic Diseases, Inborn; Heart Defects, Congenital; Humans; Kidney; Limb Deformities, Congenital; Male; Prevalence; Retrospective Studies; Spine; Trachea; Upper Extremity Deformities, Congenital
PubMed: 26498647
DOI: 10.1007/s00431-015-2655-9 -
PloS One 2014Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated...
Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.
Topics: Animals; Arnold-Chiari Malformation; Dog Diseases; Dogs; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genome; Haplotypes; Male; Quantitative Trait Loci; Skull
PubMed: 24740420
DOI: 10.1371/journal.pone.0089816 -
The International Journal of... 2005The spalt family of transcriptional repressors has been implicated in limb, heart, ear and kidney development and truncating mutations in a human gene, SALL1, result in...
The spalt family of transcriptional repressors has been implicated in limb, heart, ear and kidney development and truncating mutations in a human gene, SALL1, result in the autosomal dominant disorder Townes-Brocks syndrome. Here we show the expression pattern of the chick orthologue of the SALL1 gene, csal1, during early development. We found csal1 expression in the heart and in the pharynx, a source of inductive signals during heart development. Expression was also seen in involuting mesoderm and later in presegmented paraxial mesoderm. We also describe expression in the ectoderm and neural plate of the early embryo and subsequent expression in the neural tube.
Topics: Animals; Chick Embryo; Extremities; Gene Expression Regulation, Developmental; Heart; Homeodomain Proteins; In Situ Hybridization; Limb Buds; Mesoderm; Myocardium; Notochord; Transcription Factors; Transcription, Genetic; Zinc Fingers
PubMed: 15968588
DOI: 10.1387/ijdb.051985ds -
Mechanisms of Development Jun 2001SALL1 is one of three human homologues of the Drosophila region-specific homeotic gene spalt (sal). Mutations of SALL1 on chromosome 16q12.1 cause Townes--Brocks...
SALL1 is one of three human homologues of the Drosophila region-specific homeotic gene spalt (sal). Mutations of SALL1 on chromosome 16q12.1 cause Townes--Brocks syndrome (TBS) which is characterized by defects in multiple organ systems including limbs, ears, kidneys and anus. Here, we have analyzed the expression of the mouse homologue of SALL1 (Sall1) during early embryogenesis. Sall1 expression is very prominent in the developing brain and the limbs. Other sites of expression include the meso- and metanephros, lens, olfactory bulbs, heart, primitive streak and the genital tubercle. Hence, Sall1 expression to a large degree reflects the structures affected in human TBS.
Topics: Animals; Brain; Cloning, Molecular; Embryo, Mammalian; Extremities; In Situ Hybridization; Mice; RNA; Time Factors; Tissue Distribution; Transcription Factors
PubMed: 11404093
DOI: 10.1016/s0925-4773(01)00364-1