Prenatal mr findings of the middle interhemispheric. Transcriptional profile of shsy5y human neuroblastoma. Zic2 controls cerebellar development in cooperation with. Neurulation is susceptible to the perturbation of fundamental cell behaviors such as mitosis juriloff and harris, 2000. Consistently in humans, clinical data has revealed that mutations in human zic2 account for a large number of cases of the neural. During cns development, combinatorial expression of transcription factors controls neuronal subtype identity and subsequent axonal trajectory. Since zebrafish with reduced zic2a levels display hpelike forebrain defects sanek and grinblat, 2008, sanek et al. The cloning of the mouse zic2 gene, homologous recombination, and generation of chimera mice were performed as described 5, 7. Emerging roles for zic genes in early development american. Background holoprosencephaly hpe, the most common malformation of the human forebrain, may be due to mutations in genes associated with nonsyndromic hpe. Materials and methods targeted mutation of mouse zic2.
Here, we show that midline bending is not essential for spinal closure since, in its absence, the neural tube can close by a default mechanism involving. Zic2 patterns binocular vision by specifying the uncrossed retinal. Aruga j, minowa o, sugimoto t, ohno y, noda t, mikoshiba k 2000 zic2 regulates the kinetics of neurulation. Here we show that reduced expression knockdown of mouse zic2 causes neurulation delay, resulting in hpe and spina bifida. Holoprosencephaly is the most common brain malformation in humans and it is a complex genetic disorder. Neurulation is also the developmental event that is the most sensitive to telomere loss and chromosomal instability herrera et al. Holoprosencephaly orphanet journal of rare diseases. Similarly, zic2 mutant mice exhibit holoprosencephaly in homozygosis and behavioral and morphological schizophrenic phenotypes associated with forebrain defects in heterozygosis. The zic genes encode a family of transcription factors with important roles during early development. A recent study has shown that ephb1, a receptor for ephrin2, guides selected retinofugal axons into the pathway from the retina to the cerebral hemisphere on the same side of the body. The middle interhemispheric variant of holoprosencephaly mih was first described in 1993.
Y ohno, t noda, k mikoshibazic2 regulates the kinetics of neurulation. Murine zic genes zic15 are expressed in the dorsal hindbrain and in periotic mesenchyme pom adjacent to the developing inner ear. We show that loss of maternal zic2 results in persistent and increased expression of xenopus nodalrelated xnr genes, except for xnr4, and overall increased nodal signaling. Jun 17, 2011 zic2 zic2 is a member of the zic family of zinc finger proteins, which function as transcriptional regulators with critical roles in neural development 1,2,3,4,5. Because the zic2 knockdown mouse is the first mutant with hpe and spina bifida to survive to the perinatal period, the mouse will promote analyses of not only the neurulation but also the pathogenesis of human hpe. Site specific mutation of the zic2locus by microinjection of. Another shows that the transcription factor zic2 is also important in this uncrossed pathway. Holoprosencephaly hpe is the most common malformation of the human forebrain, and may be due to cytogenetic anomalies, teratogens, occur in the context of a syndrome, or be due to mutations in single genes associated with nonsyndromic hpe. It belongs to the zinc finger protein of the cerebellum zic family of genes that share a c2h2type zinc finger domain, similar. Zic genes are involved in developmental signaling pathways in many organ systems, including the ear, although their exact roles havent been fully elucidated. Prenatal mr findings of the middle interhemispheric variant.
Regulatory genes designating the routing of retinal ganglion cell rgc axons at the optic chiasm to the appropriate hemisphere, a pattern critical for proper binocular vision, have not been identified. Zic2 controls cerebellar development in cooperation with zic1. Among the five mammalian zic genes, zic2 and zic3 have critical. It has been involved in neural tube and neural crest formation. Depletion of maternal zic2 from oocytes, using antisense oligonucleotides, caused exogastrulation, anterior truncations and axial defects. Nagai t, aruga j, minowa o, sugimoto t, ohno y, noda t, mikoshiba k 2000 zic2 regulates the kinetics of neurulation. Mutation in human zic2, a zinc finger protein homologous to drosophila odd paired, causes holoprosencephaly hpe, which is a common. Mutation in human zic2, a zinc finger protein homologous to drosophila oddpaired, causes holoprosencephaly hpe, which is a common, severe malformation of the brain in humans. Defects in such processes are a common cause of congenital malformation syndromes, and rapid progress is being made in elucidating their embryological and genetic. Mouse zic genes encode zinc finger proteins and are expressed in the developing and mature cns. Also referred to as syntelencephaly, this malformation consists of an abnormal midline connection of the cerebral hemispheres in the posterior frontal and parietal regions, with interhemispheric separation of the basal forebrain, anterior frontal lobes, and occipital regions. However, it still remains to be answered how zic2 regulates the progression of neurulation, or how the neurulation delay leads to ntd such as spina bifida.
To search for zic2 target genes, we compared the gene expression profiles of vt retinal segments of embryonic day e16. Charles community college dan reid, champaign chs slides revised by xin song for spring 2020 term. Nasal fistula, epidermal cyst and hypernatremia in a girl. Wt and zic2 mutant embryos zic2 kdkd nagai et al, 2000. This report examines the role of zic1, zic2, and zic4 during inner ear development in. Zic2 knockdown mice show a strong holoprosencephaly phenotype in which the cerebral hemispheres are fused, and structures derived from the dorsal midline of forebrain are missing or reduced. Holoprosencephaly orphanet journal of rare diseases full text.
Read zic2 mutations are seen in holoprosencephaly and not partial rhombencephalosynapsis, american journal of medical genetics part a on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. The neural plate then infolds to form a neural keel and then a neural rod with no lumen 46, 47. First occurrence of aprosencephalyatelencephaly and. Rhombencephalosynapsis is a malformation deserving of further. Toxoplasma rhoptry protein 16 rop16 is crucial in the hostpathogen interaction by acting as a virulent factor during invasion.
Pnas is the worlds mostcited multidisciplinary scientific serial. To our knowledge, this is the first case of the rare mih variant to be diagnosed in utero by use of ultrafast mr imaging and one of the few such reports to document gross and. Zic1 regulates the patterning of vertebral arches in cooperation with gli3. Zic2 regulates the kinetics of neurulation europe pmc. To improve understanding of the molecular function underlying the effect of rop16 on host cells, the present study analyzed the transcriptional profile of genes in the rop16. It is estimated to occur in 116,000 live births and 1250 conceptuses. Towards a cellular and molecular understanding of neurulation. Since little is known about zic gene expression in chick embryos, we have characterized the expression patterns of the zic1, zic2, zic3, and zic4 zic14 genes during neurulation and somitogenesis. The process of neurulation in zebrafish starts with the formation of the neural plate during gastrulation.
By takeharu nagai, jun aruga, osamu minowa, takashi sugimoto, yoshiki ohno, tetsuo noda and katsuhiko mikoshiba. Expression of the zic1, zic2, zic3, and zic4 genes. However, the disruption of zic1, a strong homolog of zic2 that has an overlapping expression pattern, results in cerebellar malformation with no apparent abnormalities in the forebrain or in posterior neuropore. Vertebrate neurulation is a complex morphogenetic process that requires the. Zic5 mrna was first detected at the bud stage overlapping with the anterior neural edge in an area that was very restricted as compared to the zic2. We report a case of the middle interhemispheric variant of holoprosencephaly mih with noncleavage of the posterior portion of the frontal lobes and the parietal regions in a fetus at 22 weeks gestation. Mutation in human zic2, a zinc finger protein homologous to drosophila oddpaired, causes holoprosencephaly hpe, which is a common. Aug 12, 2015 human mutations in zic2 have been identified in patients with holoprosencephaly and schizophrenia. Chung peter chieh, university of waterloo hana elsamad, ucsb john d. The transcription factor zic2 is member of zic family, at early stages it has been involved in several processes during embryonic development and later on in morphogenesis and organogenesis. Nov 01, 2011 read rhombencephalosynapsis is a malformation deserving of further study, american journal of medical genetics part a on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
During neurulation the crest cells undergo an epithelial to. As mouse neurulation progresses along the spinal axis, there is a shift from midline neural plate bending to dorsolateral bending. These results suggest that the zic2 expression level is crucial for the timing of neurulation. Human mutations in zic2 have been identified in patients with holoprosencephaly and schizophrenia. Zic2 and zic3 synergistically control neurulation and segmentation. Folic acid supplementation at the time of neurulation is very likely to galvanize an. Expression of the zic1, zic2, zic3, and zic4 genes in early chick embryos. Zic2 is required for neural crest formation and hindbrain patterning. Nodal signaling regulates closure of the anterior neural tube. Differentiation of the most dorsal neural plate, which gives rise to both roof plate and neural crest cells, also was delayed as indicated by the expression lag of a roof plate marker, wnt3a. The role of zic genes in inner ear development in the. Chemical kinetics lecture notes edited by john reif from ppt lectures by. Mikoshibazic2 regulates the kinetics of neurulation. Rhombencephalosynapsis is a malformation deserving of.
Furthermore, recent papers by mikoshiba and coworkers 34,37,38 indicate that deficiency of expression in other members of the zic family of genes in the mouse results in phenotypes with skeletal abnormalities and neurulation defects, as well. Zic2 controls the migration of specific neuronal populations. Zic2zic2 is a member of the zic family of zinc finger proteins, which function as transcriptional regulators with critical roles in neural development 1,2,3,4,5. Nodal signaling is required for closure of the anterior. We used in situ hybridization to analyze the expression patterns of the zic14 genes during. Zic2 mutations are seen in holoprosencephaly and not partial. We report on a patient with holoprosencephaly caused by a rare zic2 mutation presenting a bifid nose associated with a nasal fistula and an epidermal cyst, besides hypernatremia. Many of the developmental mechanisms and molecular pathways that underlie fundamental features of body patterning are shared by all vertebrates, and some have even been conserved across evolution from invertebrates to vertebrates. More than 80 mutant mouse genes disrupt neurulation and allow an indepth analysis of the underlying. Jul 28, 2003 ntd have been observed in mice deficient for the zic family genes, zic1, zic2, and zic3. In zic2 we identified a deletion of one codon that encodes an alanine residue located in the amino terminal alanine stretch of the. Proc natl acad sci u s a 97, 1618 1623 105 nagai, t.
Read rhombencephalosynapsis is a malformation deserving of further study, american journal of medical genetics part a on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Genetic variants in zic1, zic2, and zic3 are not major risk. The middle interhemispheric variant of holoprosencephaly. Link between the causative genes of holoprosencephaly. Expression of the zic1, zic2, zic3, and zic4 genes in. Jul 01, 2000 furthermore, recent papers by mikoshiba and coworkers 34,37,38 indicate that deficiency of expression in other members of the zic family of genes in the mouse results in phenotypes with skeletal abnormalities and neurulation defects, as well. Apr 02, 2001 zic2 mutations were encountered in three of the 49 probands from families with more than one affected 6%, and in 14 of 460 sporadic cases of hpe 3%. Ntd have been observed in mice deficient for the zic family genes, zic1, zic2, and zic3. Maternal xenopus zic2 negatively regulates nodalrelated. In addition the development of neural crest derivatives such as dorsal root ganglion was impaired. Holoprosencephaly hpe is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. Zic2 regulates the expression of sert to modulate eye. Objective to characterise genetic and clinical findings in patients with zic2 mutations.
Zic2 mutations were encountered in three of the 49 probands from families with more than one affected 6%, and in 14 of 460 sporadic cases of hpe 3%. Initially during mouse neural development zic2 is expressed. Maternal xenopus zic2 negatively regulates nodalrelated gene. Reduced expression of zic2 in mice results in spina bifida and holoprosencephaly. In humans, mutations in zic2 are associated with hpe and a mild but characteristic set of craniofacial dysmorphologies solomon et al. Neural tube closure is a fundamental embryonic event whose molecular regulation is poorly understood. Mutations in zic2, located on chromosome q32, are a common cause of nonsyndromic, nonchromosomal hpe. An important role has been attributed to zic2 during the development of the neural system. The patient was a 1 year and 4 months old girl that developed an important neuropsychomotor delay. Genetic variants in zic1, zic2, and zic3 are not major. One of the causal genes for holoprosencephaly hpe is zic2 hpe5. During the development of xenopus laevis, maternal mrnas and proteins stored in the egg direct early patterning events such as the specification of the dorsoventral axis and primary germ layers.
Systematic sequencing of the entire coding region of the shh, zic2, tgif, and six3 genes has been performed in a series of 210 nonchromosomal hpe probands including 56 patients reported previously. Zic2 mutations are seen in holoprosencephaly and not. Roles of zic2 in regulation of pluripotent stem cells. Despite the devastating effects of mutations in zic2, the cellular and molecular mechanisms that provoke zic2. These results suggest that zic2 regulates the progression of neurulation. The expression of the mouse zic1, zic2, and zic3 gene suggests an essential role for zic genes in body pattern formation. In conclusion, multiple lines of evidence are presented demonstrating that zic2 is required for the normal development of neural tissue. Site specific mutation of the zic2locus by microinjection.