<p> Down syndrome (DS) is a complex genetic disorder caused by
the triplication of human chromosome 21 (Hsa21). The presence of an extra copy
of an entire chromosome greatly disrupts the copy number and expression of over
350 protein coding genes. This gene dosage imbalance has far-reaching effects on
normal development and aging, leading to cognitive and skeletal defects that
emerge earlier in life than the general population.</p>
<p> The present
study begins by characterizing skeletal development in young male Ts65Dn mice to
test the hypothesis that skeletal defects in male Ts65Dn mice are developmental
in nature.Femurs from young mice ranging from postnatal day 12- to 42-days of
age (P12-42) were measured and analyzed by microcomputed tomography (μCT). Cortical
defects were present generally throughout development, but trabecular defects emerged
at P30 and persisted until P42. </p>
<p> The gene <i>Dual-specificity
tyrosine-regulated kinase 1a </i>(<i>Dyrk1a</i>) is triplicated in both
DS and in Ts65Dn mice and has been implicated as a putative cause of both
cognitive and skeletal defects. To test the hypothesis that trisomic <i>Dyrk1a</i>
is related to the emergence of trabecular defects at P30, expression of <i>Dyrk1a</i>
in the femurs of male Ts65Dn mice was quantified by qPCR. Expression was shown
to fluctuate throughout development and overexpression generally aligned with
the emergence of trabecular defects at P30.</p>
<p> The growth
rate in trabecular measures between male Ts65Dn and euploid littermates was
similar between P30 and P42, suggesting a closer look into cellular mechanisms
at P42. Assessment of proliferation of BMSCs, differentiation and activity of
osteoblasts showed no significant differences between Ts65Dn and euploid
cellular activity, suggesting that the cellular microenvironment has a greater
influence on cellular activity than genetic background.</p>
These
data led to the hypothesis that reduction of <i>Dyrk1a</i> gene expression and
pharmacological inhibition of DYRK1A could be executed during a critical period
to prevent the emergence of trabecular defects at P30. To tests this hypothesis,
doxycycline-induced cre-lox recombination to reduce <i>Dyrk1a</i> gene copy
number or the DYRK1A inhibitor CX-4945 began at P21. The results of both
genetic and pharmacological interventions suggest that trisomic <i>Dyrk1a</i>
does not influence the emergence of trabecular defects up to P30. Instead, data
suggest that the critical window for the rescue of trabecular defects lies
between P30 and P42.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/14842548 |
| Date | 06 August 2021 |
| Creators | Jonathan Mark LaCombe (11022450) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/DYRK1A-RELATED_TRABECULAR_DEFECTS_IN_MALE_TS65DN_MICE_EMERGE_DURING_A_CRITICAL_DEVELOPMENTAL_WINDOW/14842548 |
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