Neural stem and progenitor cell (NPC) fate specification is a crucial component of central nervous system development, and the myriad signaling pathways that guide it are poorly understood. In my thesis work, I aimed to elucidate signaling mechanisms of the bone morphogenetic protein family (BMP) and some of its targets on astrocyte differentiation and neural stem cell maintenance. While BMP signaling was initially identified in ossification processes, it has subsequently been discovered to play a major role in NPC fate determination. However, these effects change over the course of development, and the ranges of effects are extremely wide. To address this, my lab has focused our studies on identifying downstream targets and mechanisms of BMP signaling. Here, we first utilized a microarray to identify genes upregulated in astrocytes generated from BMP4 treatment, and enriched in comparison to neural stem cells. We identified HtrA1 as one such gene, and found it to be expressed in astrocytes but not stem cells, indicating its potential use as an astrocytic marker. Additionally, we found HtrA1 to regulate astrocyte maturation rate, as well as injury response. To identify immediate regulators of BMP4 signaling effects on NPC fate, we then conducted RNA sequencing on neural progenitor cells with different BMP receptor subunits deleted, which were treated with BMP4 for a short duration. The large number of different genes that are differentially regulated in the absence of individual BMP receptors indicate unique functions that have not been properly parsed apart in the past. BMP receptor type 1 subunits may be responsible for some of the variation in BMP effects. Our identification of short-term BMP signaling targets flagged several pathways as BMP-regulated, including Hippo signaling. Our last section of studies described here therefore sought to examine the intersection of BMP and Hippo signaling at the level of Hippo pathway transcriptional factors. BMP upregulates the Hippo effector Ww-domain containing transcription regulator 1 (TAZ), but not the effector Yes-associated protein (YAP). TAZ, but not YAP, promotes astrocyte differentiation of NPCs, and YAP and TAZ together regulate the morphology of BMP-generated astrocytes. Altogether, these studies demonstrate some of BMP’s signaling targets and their effects on NPC fate specification, particularly towards astrocyte differentiation, as well as the need for further studies to identify other downstream BMP mechanisms.

Creator

• Chen, Jessie

DOI

• https://doi.org/10.21985/n2-n0sw-h838

Subject

• Neurosciences

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15191
• etdadmin_upload_755327

Keyword

• YAP
• Integrin
• neural stem cell
• TAZ
• BMP
• HtrA1

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright