Publications by authors named "Stephania Macchiarulo"

4 Publications

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and act in concert to modulate the fate of neurosensory cells of the mouse otic vesicle.

Biol Open 2017 Oct 15;6(10):1472-1482. Epub 2017 Oct 15.

Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA

The domain within the otic vesicle (OV) known as the neurosensory domain (NSD), contains cells that will give rise to the hair and support cells of the otic sensory organs, as well as the neurons that form the cochleovestibular ganglion (CVG). The molecular dynamics that occur at the NSD boundary relative to adjacent OV cells is not well defined. The transcription factor gene expression pattern is complementary to the NSD, and inactivation results in expansion of the NSD and expression of the Notch ligand, Jag1 mapping, in part of the NSD. To shed light on the role of in NSD development, as well as to test whether and might genetically interact to regulate this process, we inactivated within the expression domain using a knock-in allele. We observed an enlarged neurogenic domain marked by a synergistic increase in expression of and other proneural transcription factor genes in double and conditional loss-of-function embryos. We noted that neuroblasts preferentially expanded across the medial-lateral axis and that an increase in cell proliferation could not account for this expansion, suggesting that there was a change in cell fate. We also found that inactivation of with resulted in failed development of the cristae and semicircular canals, as well as notably fewer hair cells in the ventral epithelium of the inner ear rudiment when inactivated on a null background, compared to mutant embryos. We propose that loss of expression of and within the expression domain tips the balance of cell fates in the NSD, resulting in an overproduction of neuroblasts at the expense of non-neural cells within the OV.
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http://dx.doi.org/10.1242/bio.027359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665468PMC
October 2017

Tbx1 is required autonomously for cell survival and fate in the pharyngeal core mesoderm to form the muscles of mastication.

Hum Mol Genet 2014 Aug 4;23(16):4215-31. Epub 2014 Apr 4.

Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA,

Velo-cardio-facial/DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a congenital anomaly disorder characterized by craniofacial anomalies including velo-pharyngeal insufficiency, facial muscle hypotonia and feeding difficulties, in part due to hypoplasia of the branchiomeric muscles. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on chromosome 22q11.2, results in reduction or loss of branchiomeric muscles. To identify downstream pathways, we performed gene profiling of microdissected pharyngeal arch one (PA1) from Tbx1(+/+) and Tbx1(-/-) embryos at stages E9.5 (somites 20-25) and E10.5 (somites 30-35). Basic helix-loop-helix (bHLH) transcription factors were reduced, while secondary heart field genes were increased in expression early and were replaced by an increase in expression of cellular stress response genes later, suggesting a change in gene expression patterns or cell populations. Lineage tracing studies using Mesp1(Cre) and T-Cre drivers showed that core mesoderm cells within PA1 were present at E9.5 but were greatly reduced by E10.5 in Tbx1(-/-) embryos. Using Tbx1(Cre) knock-in mice, we found that cells are lost due to apoptosis, consistent with increase in expression of cellular stress response genes at E10.5. To determine whether Tbx1 is required autonomously in the core mesoderm, we used Mesp1(Cre) and T-Cre mesodermal drivers in combination with inactivate Tbx1 and found reduction or loss of branchiomeric muscles from PA1. These mechanistic studies inform us that Tbx1 is required upstream of key myogenic genes needed for core mesoderm cell survival and fate, between E9.5 and E10.5, resulting in formation of the branchiomeric muscles.
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http://dx.doi.org/10.1093/hmg/ddu140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103673PMC
August 2014

GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.

PLoS One 2011 24;6(8):e23656. Epub 2011 Aug 24.

Department of Cell Biology & Anatomy, New York College of Medicine, Valhalla, New York, United States of America.

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023656PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161054PMC
January 2012

Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination.

Nat Immunol 2009 Apr 22;10(4):420-6. Epub 2009 Feb 22.

Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Immunoglobulin class-switch recombination (CSR) requires activation-induced cytidine deaminase (AID). Deamination of DNA by AID in transcribed switch (S) regions leads to double-stranded breaks in DNA that serve as obligatory CSR intermediates. Here we demonstrate that the catalytic and regulatory subunits of protein kinase A (PKA) were specifically recruited to S regions to promote the localized phosphorylation of AID, which led to binding of replication protein A and subsequent propagation of the CSR cascade. Accordingly, inactivation of PKA resulted in considerable disruption of CSR because of decreased AID phosphorylation and recruitment of replication protein A to S regions. We propose that PKA nucleates the formation of active AID complexes specifically on S regions to generate the high density of DNA lesions required for CSR.
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http://dx.doi.org/10.1038/ni.1708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169875PMC
April 2009