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Fard, Shahrzad Shirazi
Alternative names
Publications (8 of 8) Show all publications
Boije, H., Fard, S. S., Edqvist, P.-H. & Hallböök, F. (2016). Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease. Frontiers in Neuroanatomy, 10, Article ID 77.
Open this publication in new window or tab >>Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease
2016 (English)In: Frontiers in Neuroanatomy, ISSN 1662-5129, E-ISSN 1662-5129, Vol. 10, article id 77Article, review/survey (Refereed) Published
Abstract [en]

Thorough investigation of a neuronal population can help reveal key aspects regarding the nervous system and its development. The retinal horizontal cells have several extraordinary features making them particularly interesting for addressing questions regarding fate assignment and subtype specification. In this review we discuss and summarize data concerning the formation and diversity of horizontal cells, how morphology is correlated to molecular markers, and how fate assignment separates the horizontal lineage from the lineages of other retinal cell types. We discuss the novel and unique features of the final cell cycle of horizontal cell progenitors and how they may relate to retinoblastoma carcinogenesis.

Keywords
cell fate, cell cycle regulation, chicken, development, DNA damage, neuronal subtype, retinoblastoma, zebrafish
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-301132 (URN)10.3389/fnana.2016.00077 (DOI)000379879400001 ()
Funder
Swedish Research Council
Available from: 2016-08-22 Created: 2016-08-18 Last updated: 2017-11-28Bibliographically approved
Fard, S. S., Blixt, M. & Hallböök, F. (2015). The p53 co-activator Zac1 neither induces cell cycle arrest nor apoptosis in chicken Lim1 horizontal progenitor cells. Cell Death Discovery, 1, Article ID 15023.
Open this publication in new window or tab >>The p53 co-activator Zac1 neither induces cell cycle arrest nor apoptosis in chicken Lim1 horizontal progenitor cells
2015 (English)In: Cell Death Discovery, ISSN 2058-7716, Vol. 1, article id 15023Article in journal (Refereed) Published
Abstract [en]

Chicken horizontal progenitor cells are able to enter their final mitosis even in the presence of DNA damage despite having a functional p53-p21 system. This suggests that they are resistant to DNA damage and that the regulation of the final cell cycle of horizontal progenitor cells is independent of the p53-p21 system. The activity of p53 is regulated by positive and negative modulators, including the zinc finger containing transcription factor Zac1 (zinc finger protein that regulates apoptosis and cell cycle arrest). Zac1 interacts with and enhances the activity of p53, thereby inducing cell cycle arrest and apoptosis. In this work, we use a gain-of-function assay in which mouse Zac1 (mZac1) is overexpressed in chicken retinal progenitor cells to study the effect on the final cell cycle of horizontal progenitor cells. The results showed that overexpression of mZac1 induced expression of p21 in a p53-dependent way and arrested the cell cycle as well as triggered apoptosis in chicken non-horizontal retinal progenitor cells. The negative regulation of the cell cycle by mZac1 is consistent with its proposed role as a tumour-suppressor gene. However, the horizontal cells were not affected by mZac1 overexpression. They progressed into S- and late G2/M-phase despite overexpression of mZac1. The inability of mZac1 to arrest the cell cycle in horizontal progenitor cells support the notion that the horizontal cells are less sensitive to events that triggers the p53 system during their terminal and neurogenic cell cycle, compared with other retinal cells. These properties are associated with a cell that has a propensity to become neoplastic and thus with a cell that may develop retinoblastoma.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Neurology Developmental Biology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-279034 (URN)10.1038/cddiscovery.2015.23 (DOI)
Available from: 2016-02-28 Created: 2016-02-28 Last updated: 2017-02-17Bibliographically approved
Fard, S. S., All-Ericsson, C. & Hallböök, F. (2014). The heterogenic final cell cycle of chicken retinal Lim1 horizontal cells is not regulated by the DNA damage response pathway. Cell Cycle, 13(3), 408-417
Open this publication in new window or tab >>The heterogenic final cell cycle of chicken retinal Lim1 horizontal cells is not regulated by the DNA damage response pathway
2014 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 3, p. 408-417Article in journal (Refereed) Published
Abstract [en]

Cells with aberrations in chromosomal ploidy are normally removed by apoptosis. However, aneuploid neurons have been shown to remain functional and active both in the cortex and in the retina. Lim1 horizontal progenitor cells in the chicken retina have a heterogenic final cell cycle, producing some cells that enter S-phase without proceeding into M-phase. The cells become heteroploid but do not undergo developmental cell death. This prompted us to investigate if the final cell cycle of these cells is under the regulation of an active DNA damage response. Our results show that the DNA damage response pathway, including gamma-H2AX and Rad51 foci, is not triggered during any phase of the different final cell cycles of horizontal progenitor cells. However, chemically inducing DNA adducts or double-strand breaks in Lim1 horizontal progenitor cells activated the DNA damage response pathway, showing that the cells are capable of a functional response to DNA damage. Moreover, manipulation of the DNA damage response pathway during the final cell cycle using inhibitors of ATM/ATR, Chk1/2, and p38MAPK, neither induced apoptosis nor mitosis in the Lim1 horizontal progenitor cells. We conclude that the DNA damage response pathway is functional in the Lim1 horizontal progenitor cells, but that it is not directly involved in the regulation of the final cell cycle that gives rise to the heteroploid horizontal cell population.

Keywords
Rad51, ATM/ATR, retina, apoptosis, cell cycle regulation, H2AX, DNA damage response, programmed cell death, cisplatin
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-223571 (URN)10.4161/cc.27200 (DOI)000332833400016 ()
Available from: 2014-04-24 Created: 2014-04-22 Last updated: 2017-12-05Bibliographically approved
Shirazi Fard, S., Thyselius, M., All-Ericsson, C. & Hallböök, F. (2014). The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest. Cell Cycle, 13(23), 3698-3706
Open this publication in new window or tab >>The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest
2014 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 23, p. 3698-3706Article in journal (Refereed) Published
Abstract [en]

For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.

Keywords
ATM/ATR, cell cycle regualtion, cyclinB1-Cdk1, Nutlin3a, retina
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-222542 (URN)10.4161/15384101.2014.964985 (DOI)000348329200013 ()25483080 (PubMedID)
Available from: 2014-04-11 Created: 2014-04-11 Last updated: 2018-01-11Bibliographically approved
Boije, H., Ring, H., Fard, S. S., Grundberg, I., Nilsson, M. & Hallbook, F. (2013). Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina. Journal of Molecular Neuroscience, 51(2), 615-628
Open this publication in new window or tab >>Alternative Splicing of the Chromodomain Protein Morf4l1 Pre-mRNA Has Implications on Cell Differentiation in the Developing Chicken Retina
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2013 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 2, p. 615-628Article in journal (Refereed) Published
Abstract [en]

The proliferation, cell cycle exit and differentiation of progenitor cells are controlled by several different factors. The chromodomain protein mortality factor 4-like 1 (Morf4l1) has been ascribed a role in both proliferation and differentiation. Little attention has been given to the existence of alternative splice variants of the Morf4l1 mRNA, which encode two Morf41l isoforms: a short isoform (S-Morf4l1) with an intact chromodomain and a long isoform (L-Morf4l1) with an insertion in or in the vicinity of the chromodomain. The aim of this study was to investigate if this alternative splicing has a function during development. We analysed the temporal and spatial distribution of the two mRNAs and over-expressed both isoforms in the developing retina. The results showed that the S-Morf4l1 mRNA is developmentally regulated. Over-expression of S-Morf4l1 using a retrovirus vector produced a clear phenotype with an increase of early-born neurons: retinal ganglion cells, horizontal cells and cone photoreceptor cells. Over-expression of L-Morf4l1 did not produce any distinguishable phenotype. The over-expression of S-Morf4l1 but not L-Morf4l1 also increased apoptosis in the infected regions. Our results suggest that the two Morf4l1 isoforms have different functions during retinogenesis and that Morf4l1 functions are fine-tuned by developmentally regulated alternative splicing. The data also suggest that Morf4l1 contributes to the regulation of cell genesis in the retina.

Keywords
Acetylation, Avian, Chromatin structure, Development, HAT, HDAC, Isoform, Histon, MRG15, MRGX, Neuron, RCAS, Retina, Splicing, Virus vector
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209850 (URN)10.1007/s12031-013-0034-4 (DOI)000324637200047 ()
Available from: 2013-10-28 Created: 2013-10-28 Last updated: 2017-12-06Bibliographically approved
Fard, S. S., Jarrin, M., Boije, H., Fillon, V., All-Eriksson, C. & Hallböök, F. (2013). Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome. PLoS ONE, 8(3), e59133
Open this publication in new window or tab >>Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e59133-Article in journal (Refereed) Published
Abstract [en]

Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs) exit the cell cycle. We have used markers for S-and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal) mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-200114 (URN)10.1371/journal.pone.0059133 (DOI)000317562100081 ()
Available from: 2013-05-22 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
Ring, H., Mendu, S. K., Shirazi-Fard, S., Birnir, B. & Hallböök, F. (2012). GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      . PLoS ONE, 7(5), e36874
Open this publication in new window or tab >>GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36874-Article in journal (Refereed) Published
Abstract [en]

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABA(A) receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABA(A) receptor system. To quantify the effects on proliferation by GABA(A) receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABA(A) receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABA(A) receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl-transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABA(A) receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABA(A) receptors. This supported the depolarising role for the GABA(A) receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABA(A) receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27(KIP1), along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27(KIP1) after inhibition of either the GABA(A) receptors or the L-type VGCCs suggests a link between the GABA(A) receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle. 

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-172512 (URN)10.1371/journal.pone.0036874 (DOI)000305336100070 ()
Available from: 2012-04-11 Created: 2012-04-10 Last updated: 2018-01-12Bibliographically approved
Hellström, A. R., Watt, B., Fard, S. S., Tenza, D., Mannström, P., Narfström, K., . . . Andersson, L. (2011). Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation. PLoS Genetics, 7(9), e1002285
Open this publication in new window or tab >>Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation
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2011 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 9, p. e1002285-Article in journal (Refereed) Published
Abstract [en]

PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel(-/-)). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel(-/-) melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-161066 (URN)10.1371/journal.pgen.1002285 (DOI)000295419100034 ()
Available from: 2011-11-14 Created: 2011-11-07 Last updated: 2011-11-15Bibliographically approved
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