Primordial Dwarfism Gene Maintains Lin28 Expression to Safeguard Embryonic Stem Cells from Premature Differentiation

Abstract

Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size.

Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment

“…Moreover, our results suggest that in neurons, knockdown of LARP7 does not increase Pol2-driven transcription of a CRE-regulated reporter construct. Likewise, no general effects on mRNA expression were observed in LARP7-depleted mouse ES cells (67). Conversely, our findings suggest that, at least, neurological symptoms of Alazami syndrome are caused by translational deficits and/or nucleolar stress.…”

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

“…Indeed, both of the 7SK-stabilizing factors underwent full downregulation during neonatal megakaryopoiesis ( Figure 2E and Supplemental Figure 3A). Numerous studies have documented tight coupling of 7SK snRNA levels with its stabilizing factors (26)(27)(28)(29)(30). However, the stabilizing factors' decline in neonatal megakaryocytes occurred in the absence of a proportionate drop in 7SK snRNA levels, which remained 2.5-fold higher than adult levels ( Figure 2F and Supplemental Figure 3B).…”

Visualization of Positive Transcription Elongation Factor b (P-TEFb) Activation in Living Cells

“…Components of the 7SK snRNP also play critical roles in gene expression during stem cell differentiation and in cancer (43)(44)(45)(46)(47)(48)(49). Moreover, increased P-TEFb activity and the subsequent synthesis of its inhibitor HEXIM1 represent critical common steps for many anti-cancer and anti-inflammatory drugs (27,37,50).…”