<p>The relationship between gene copy
number and protein expression levels has not thoroughly been examined in humans
or mouse models of Down syndrome (DS) in relationship to developmental changes
in the trisomic brain. Found on human
chromosome 21 (Hsa21) and triplicated in DS, Dual-specificity
tyrosine-phosphorylated regulated kinase 1A (<i>DYRK1A)</i> has been linked in
DS to neurological deficits by restricting cell growth and proliferation. Little information exists regarding DYRK1A
during perinatal development and how its expression may lead to cognitive
deficits, and none exists that explores the gene-to-protein relationship during
these critical time periods. This study
aims to 1) Quantify variable
DYRK1A expression across development as a function of age, sex, and brain
region in trisomic Ts65Dn mice compared to euploid counterparts and 2)
establish that the spatiotemporal pattern of developmental DYRK1A in the brain
is not influenced solely by gene copy number, and that reduction of <i>Dyrk1a</i>
in euploid and trisomic mice does not result in a corresponding global
reduction of DYRK1A expression. DYRK1A
was quantified in three areas of the postnatal brain at seven ages using the
Ts65Dn mouse, the most studied model of DS, and found that trisomic expression
is significantly increased on postnatal day ([P]6), declining by the third week
to near euploid levels. We also
uncovered a sexual dimorphic expression of DYRK1A when comparing animals of
different sexes within the same genotype.
Data from <i>Dyrk1a</i> knockdown mice indicated that reducing only <i>Dyrk1a</i>
in euploid and in otherwise trisomic animals yields highly variable levels of
DYRK1A, dependent on sex and tissue type, supporting the non-intuitive
relationship between gene dosage and protein expression. These data emphasize the need to
understand the age-dependent regulation of antecedent conditions that are
causing changes in <i>Dyrk1a</i> expression
in the brain.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12200321 |
| Date | 28 April 2020 |
| Creators | Laura E Hawley (8755629) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Quantifying_DYRK1A_during_perinatal_development_in_the_hippocampus_cerebral_cortex_and_cerebellum_of_the_Ts65Dn_mouse_model/12200321 |
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