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From Hematopoiesis to Neuropoiesis: Evidence of Overlapping Genetic Programs

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From Hematopoiesis to Neuropoiesis: Evidence of Overlapping Genetic Programs From hematopoiesis to neuropoiesis: Evidence of overlapping genetic programs Alexey V. Terskikh*†, Mathew C. Easterday‡, Linheng Li§, Leroy Hood§, Harley I. Kornblum‡, Daniel H. Geschwind¶, and Irving L. Weissman* *Stanford University School of Medicine, Department of Pathology, Beckman Center, Stanford, CA 94306; ‡Department of Molecular and Medical Pharmacology and Pediatrics, School of Medicine, University of California, Los Angeles, CA 90095; §University of Washington, Department of Molecular Biotechnology, Seattle, WA 98195; and ¶Neurogenetics Program and Department of Neurology, Reed Neurological Research Center, School of Medicine, University of California, Los Angeles, CA 90095-1769 Contributed by Irving L. Weissman, April 23, 2001 It is reasonable to propose that gene expression profiles of purified tissues, but not blood (21). These results suggest that different stem cells could give clues for the molecular mechanisms of stem stem cells, but not any other cells in the adult organism, may cell behavior. We took advantage of cDNA subtraction to identify retain a general self-renewing and differentiating capacity or a set of genes selectively expressed in mouse adult hematopoietic pluripotency (22) and thus it seems reasonable to propose that stem cells (HSC) as opposed to bone marrow (BM). Analysis of common basic molecular mechanisms, in addition to environ- HSC-enriched genes revealed several key regulatory gene candi- mental clues, could be responsible for self-renewal properties of dates, including two novel seven transmembrane (7TM) receptors. stem cells. Furthermore, by using cDNA microarray techniques we found a Here we approached the isolation of genes commonly and large set of HSC-enriched genes that are expressed in mouse preferentially expressed in stem cells by identifying the genes neurospheres (a population greatly enriched for neural progenitor that differentially expressed in adult HSC compared with its cells), but not present in terminally differentiated neural cells. In direct environment, BM. Furthermore, using cDNA microarray situ hybridization demonstrated that many of them, including one technology, we have identified a set of genes expressed in HSC HSC-enriched 7TM receptor, were selectively expressed in the (but not BM) that are also expressed in mouse neurospheres (but germinal zones of fetal and adult brain, the regions harboring not in terminally differentiated neural cells). In vivo, many of mouse neural stem cells. We propose that at least some of the these genes also selectively expressed in the regions of embryonic transcripts that are selectively and commonly expressed in two or and adult brain that contain central nervous system stem cells more types of stem cells define a functionally conserved group of and are the sites of continuous neurogenesis. genes evolved to participate in basic stem cell functions, including stem cell self-renewal. Materials and Methods HSC Sorting and PCR Techniques. About 3 ϫ 105 double-sorted ymphohematopoietic cells are constantly replenished by HSCs (23) from AKR͞J mice and 6 ϫ 105 BM cells were used Lcommon clonogenic precursors called hematopoietic stem to isolate RNA and make first-strand cDNA, using CLON- cells (HSC; refs. 1 and 2). HSCs are the principal cells respon- TECH’s SMART first-strand cDNA synthesis. The cDNA sub- sible for developing and maintaining lympho- and hematopoiesis traction was performed with the PCR-Select protocol (CLON- during ontogeny and after BM transplantation (3, 4). One of the TECH) after 16 cycles of PCR amplification, according to most intriguing properties of adult HSCs is a robust maintenance manufacturer’s instructions. of the dynamic equilibrium between self-renewal and differen- tiation (5). Despite extensive phenotypic and functional charac- Sequence Analysis. Analyses were performed on-line, except terization of HSCs (6, 7), little is known about the molecular clustering͞vector removal made with PHRAPP (Stanford Se- mechanisms that regulate their self-renewal and differentiation. quencing Center, Stanford, CA). The batch homology search was The likelihood that HSC function might require selective gene made with BLAST; sequence analysis and secondary structure expression was recently supported by the identification of tran- prediction was preformed by using on-line packages from the scripts enriched in mouse fetal liver hematopoietic stem cells (8). ExPASy Molecular Biology Server (http:͞͞ExPASy.CH), Eu- Central nervous system neural stem cells (NSC) have been ropean Molecular Biology Laboratory (EMBL), Institut Suisse identified in different regions of fetal and adult brain, and have de Recherches Experimentales sur le Cancer (Lausanne, Swit- come into focus as a new platform for research in neurodevel- zerland) (ISREC), and National Center for Biotechnology In- opment and neurobiology, as well as candidates for the potential formation (NCBI) web sites, including CLUSTALW (EMBL) and treatment of neurodegenerative diseases and central nervous BOXSHADE (ISREC). system injury (9–12). Similar to HSC, the NSC can self-renew and differentiate into all types of neural cells throughout life (13, Microarray Analysis and in Situ Hybridization. Microarray analysis of 14). In both rodent and man, long-term neural cultures growing HSC and WBM and in situ hybridization was performed exactly as adherent layers or as nonadherent neurospheres (NS) have as described (24). been shown to contain clonal progenitors of neurons, astrocytes, and oligodendrocytes (14, 15). Intriguingly, in the past few years several lines of evidence Abbreviations: HSC, hematopoietic stem cells; BM, bone marrow; NS, neurospheres; 7TM, indicate that both hematopoietic and neural stem cells might seven transmembrane; SVZ, subventricular zone; VZ, ventricular zone. demonstrate surprising plasticity. Highly purified HSC were Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. BG833695–BG833716 and AF385682). shown to give rise to liver tissues (16) and bone marrow (BM)-derived cells were shown to give rise to muscle cells (17); See commentary on page 7652. in addition, there are reports claiming BM origin of a different †To whom reprint requests should be addressed at: Stanford University School of Medicine, Department of Pathology, B259 Beckman Center, 279 Campus Drive, Stanford, CA 94305. type of neural cells, including mature neurons in brain (18, 19). E-mail: [email protected]. In a similar fashion, NS-derived cells were shown in one case to The publication costs of this article were defrayed in part by page charge payment. This give rise to hematopoietic cells (20) and in another case to article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. participate in the formation of many other embryonic and adult §1734 solely to indicate this fact. 7934–7939 ͉ PNAS ͉ July 3, 2001 ͉ vol. 98 ͉ no. 14 www.pnas.org͞cgi͞doi͞10.1073͞pnas.131200898 Downloaded by guest on September 26, 2021 Fig. 1. Analysis of genes found in the HB library. (A) Categorization by sequence type. (B) Functional clustering of known (or highly homologous) genes. (C) Sequence composition of 223 nonredundant contigs. Results by Northern hybridization (see Fig. 5, which is published as During mouse adulthood, virtually all hematopoietic stem cell supplemental data). In addition to strong differential expression activity is found within the c-kitϩ, Thy1.1low, Linneg/low, Sca-1ϩ in HSC, confirmed for all transcripts, most of the genes had a population of the BM (7). BM cDNA was subtracted from HSCs complex expression pattern, suggesting they play roles in other cDNA to enrich for transcripts expressed in HSCs by using the tissue and organs. In some cases (e.g., Meis1, HB44, and PCR-Select procedure (CLONTECH). The subtracted library 114͞A10), low to no expression was detected outside of the HSC (named HB) was examined by high-throughput sequencing compartment, suggesting that in adult mouse these genes could followed by the BLAST search of publicly available databases and be functioning selectively in the HSC population. sequence analysis. Clustering of 1,500 primary sequences re- Transcripts related to protease inhibitors were among the sulted in a set of 223 nonredundant contigs—some of them most abundant in the HB library. One of them, the Ctla-2␣ gene (40%) representing known genes and their homologues, others (incompletely spliced in the HB library), was found to be (41%) matching novel sequences (expressed sequence tags, selectively expressed also in activated cytotoxic T cells and to many of which originated from early embryonic tissues), and a share high homology to a cysteine protease proregion (30). substantial proportion (19%) producing no match in public Another serine protease inhibitor, Spi2A, was identified to be databases (Fig. 1 A and B). Over 95% of the contigs were specifically expressed in multipotent hematopoietic progenitor assembled from more than 1 read (up to 35 reads), suggesting an FDCP-Mix cells (31). The Spi2A variant found in HSC has minor exhaustive sequencing of the HB library (Fig. 1C). Informative aa changes (G173S, N179K, E182Q, T191M, L344Q, T356K, transcripts found in the HB library included a diverse set of novel C410S, M411E), possibly due to allelic variations. The abundant and known genes (see Table 1, which is published as supple- expression of Spi2A in HSC (at the level of ␤-actin) is highly mental data on the PNAS web site, www.pnas.org). The well
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