Transforming Growth Factor-β Is a Survival Factor for Neonate Cortical Neurons: Coincident Expression of Type I Receptors in Developing Cerebral Cortices

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional polypeptide which plays a crucial role in the regulation of cell proliferation, differentiation, and organogenesis. In the present study, we investigated the expression of signaling receptors for TGF-beta in developing mice by in situ hybridization, revealing a significant difference in the expression of TGF-beta type I and type II receptors. Unexpectedly, the TGF-beta type I receptors were exclusively expressed without any detectable expression of the TGF-beta type II receptors in developing cerebral cortices. In primary cortical neurons, a neutralizing antibody for TGF-beta significantly reduced the expression of bcl-2 and subsequently induced neuronal cell death, indicating that TGF-beta functions as a survival factor for cortical neurons in vitro. Consistent with the result of in situ hybridization, the TGF-beta, type I but not type II receptors were detected in primary cortical neurons by affinity crosslink and RT-PCR analyses. The concomitant expression of TGF-beta2 and the TGF-beta type I receptors in developing cerebral cortices suggests that the TGF-beta signaling system plays a pivotal role in neuronal differentiation and that unidentified components may be involved in TGF-beta signaling in the development of the central nervous system.

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

“…This absence of a TGF-␤1 response is puzzling but has been described previously (40). In addition, contradictory data report the neuronal expression of type II TGF-␤ receptor (32,41), which binds the ligand and then activates the TGF-␤ signaling intracellular pathway. Finally, these data are in agreement with a previous study (42), demonstrating that although TGF-␤ induced transcription of plasminogen activator inhibitor-1 in cultured astrocytes, it failed to mediate this response in cultured neurons.…”

“…The following primary antibodies were used: R7 (1:1,000) against KPI-APP proteins (17), R1736 (1:1,000) against sAPP-␣ (18), 192wt (1:500) against sAPP-␤ (19), FCA3340 (1:1,000) against human A␤40 (20), FCA3542 (1:1,000) against human A␤42, sc-146 (1:200) against human and murine TGF-␤1 (Santa Cruz Biotechnology Inc.), OX42 (1:100) against CD11b (kindly provided by Dr. Anna-Maria Planas), and anti-GFAP antibody (1:100) and M4403 (1:100) against actin (Sigma). R1742 and R600 were generated to synthetic A␤ [37][38][39][40][41][42] and A␤ [1][2][3][4][5][6][7][8][9][10] and tested against synthetic A␤ and A␤ …”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…TGFb1 is primarily expressed in the meninges, TGFb2 and TGF-b3 are expressed by neurons and radial glia, and BMP-6 is expressed by radial glia (Schluesener and Meyermann 1994;Murphy et al 2004;Ozdamar et al 2005). TbRI is expressed in the developing murine cortex, and is found postnatally along radial glial fibers, whereas TbRII is primarily expressed by neurons (Tomoda et al 1996;Miller 2003). Low concentrations of TGF-b1 in culture promote neuronal migration of immature neurons and neuroblastoma cells, whereas high concentrations impair migration.…”

“…In the normal adult rat brain TGF-b1 is expressed at low levels primarily in the meninges; however, following brain injury, the expression of TGF-b1 and the TGF-b receptors, TbRI and TbRII, is up-regulated (Lindholm et al 1992a;Tomoda et al 1996;McTigue et al 2000;Zhu et al 2000;Sometani et al 2001;Fee et al 2004). The temporal pattern of TGFb1 induction and neuronal death suggests that TGF-b1 is predominantly expressed by activated microglia infiltrating the ischemic region (Lehrmann et al 1995).…”

Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development

“…Several reports have described expression patterns of Alk5 transcript and protein in developing mouse embryos using in situ hybridization and immunohistochemistry, but Alk5 expression in the vascular endothelium has been obscured. [18][19][20] In order to investigate Alk5 expression in developing mouse embryos, and to compare it with that of Alk1, we have generated a novel Alk5-lacZ knockin mouse line. The lacZ reporter expression was detected in multiple tissues, and was generally consistent with the Alk5-expression pattern previously reported.…”