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Gene & Protein in Disease Comprehensive analysis of ZNF521/Zfp521

development, and it is required for the key downstream expression of Zfp521 can induce neural turnover in ESCs
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response of PTHrP. 19,47 In conclusion, Zfp521 can even in the presence of BMP4. In contrast, in differentiated
significantly regulate the proliferation, hypertrophy, and cultures, Zfp521-null ESCs do not undergo neural
apoptosis of growth plate chondrocytes, thus playing an switching but rather tend to stop in the ectodermal state.
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important role in longitudinal bone growth. 19 Zfp521 directly activates early neural genes through the
coactivator p300. Thus, the differentiation specificity of
5,21
4.4. Functions of ZNF521/Zfp521 in neural ES cells from the ectodermal state to the neuroectodermal
differentiation
progenitors relies on the intracellular expression and
Zfp521 is a nuclear protein containing 30 Kruppel-like activator function of Zfp521. Notably, Zfp521 over
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zinc fingers that mediate multiple protein interactions expression significantly reverses the inhibitory effect of
1,2
and regulate the transcription of various tissue/organ- BMP4, suggesting that its neuropathizing activity can
specific genes. Zfp521 can guide the transformation of override the inhibitory effect of BMP4. 21,72 Zfp521 over
embryonic stem cells (ESCs) into neural progenitor cells. expression does not significantly affect the expression of
15
Zfp521 plays an important role in the endogenous neural Smad7, a direct target gene of BMP signaling, in ESCs. 21
differentiation process of mouse ESCs. The BMP signaling
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pathway suppresses neural differentiation in ESCs. When During gastrulation, a strong expression of Zfp521 is
BMP inhibition is eliminated, most cells differentiate into detected in the ectoderm, particularly in the neuroectoderm
neurons. The process of differentiation of ESCs essentially regions, and not in the endoderm, degenerated mesoderm,
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induces the strong expression of Zfp521 in the absence of or non-neuroectoderm. Following gastrulation, Zfp521 is
the neural differentiation inhibitor BMP4, but a forced expressed only in the neuroectoderm of the rostral neural
tube. 20,72 These findings suggest that Zfp521 is an early
neural nuclear protein with strong neural differentiation-
promoting activity. Among them, the molecular pattern of
Zfp521 function is that Zfp521 is clearly associated with
the neuroectoderm-specific loci (including Sox1, Sox3, and
Pax6) (Figure 6) but not with the ESC marker gene Klf4
or Rex1, the ectoderm-specific marker gene Fgf5, or the
mesodermal marker gene Brachyury (T). Zfp521 proteins
are preferentially localized to early neuroectoderm-specific
genes over non-neural genes or to early genes associated
with ES ectoderm cells. This suggests that Zfp521 promotes
neural differentiation by activating early neuroectodermal
genes rather than by inhibiting the expression of non-
neural genes. 21
In previous studies, Zfp521 was shown to associate with
the coactivator p300 and directly induce the expression of
Figure 5. Zfp521 acts as a downstream factor of PTHR1 and regulates the
proliferation and differentiation of chondrocytes by HDAC4 binding to early neural genes. Knockdown of Zfp521 with shRNA
and antagonizing RUNX2 in pre-hypertrophic chondrocytes arrests cells at the ectodermal stage and restrains their

Figure 6. Zfp521 promotes neural differentiation by activating the expression of early neuroectodermal genes

Volume 3 Issue 3 (2024) 8 doi: 10.36922/gpd.3260