BDNF is required for the survival of differentiated geniculate ganglion neurons

“Inmammals, the neurotrophin family consists of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT-4) (Huang and Reichardt, 2001).”

“…by multiplying the number of total neuron profiles by a correction factor, to compensate for the presence of the nucleus in multiple sections (Abercrombie, 1946), according to the formula: N=n×[T/ (T×D)] where N is the estimated total number of neurons, n is the number of nuclear profiles, T…”

“Caspase-3 typically functions downstream of Bax and cleaves different substrates to facilitate cell death via DNA fragmentation (De Zio et al., 2005; Earnshaw et al., 1999).”

“Death in different neuronal types might result from the activation of varying arrays of caspases, activation of these molecules commonly results in caspase-3 activation for many neurons (Yuan and Yankner, 2000).”

“Developmental neuronal death has been attributed to a Baxdependent programmed cell death pathway (White et al., 1998).”

“The final number of neurons that comprise the geniculate ganglion is influenced by BDNF. Relative to wild-type animals, bdnf−/− mice show a significant reduction in neurons in the geniculate ganglion by birth (Conover et al., 1995; Liu et al., 1995).”

“NGF- and NT3-dependant spinal sensory neuron loss can be rescued via inhibition of the Bax-dependent cell death pathway (Patel et al., 2000, 2003).”

“The final number of neurons that comprise the geniculate ganglion is influenced by BDNF. Relative to wild-type animals, bdnf−/− mice show a significant reduction in neurons in the geniculate ganglion by birth (Conover et al., 1995; Liu et al., 1995).”

“This approach has been used successfully to examine changes in ganglion neuron number followingmanipulations of neurotrophins (Agerman et al., 2003; ElShamy and Ernfors, 1997; Erickson et al., 2001, 1996).”

“BdnflacZ mice were a kind gift from Kevin Jones (Dept. of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO, USA) (Baquet et al., 2005; Gorski et al., 2003a,b).”

“For example, neurons in the DRG of nt-3−/− mice are first lost between E11 and E13, which is well before target innervation (Farinas et al., 1996).”

“Early in geniculate ganglion development, cells are added rapidly (Altman and Bayer, 1982).”

“NGF- and NT3-dependant spinal sensory neuron loss can be rescued via inhibition of the Bax-dependent cell death pathway (Patel et al., 2000, 2003).”

“BdnflacZ mice were a kind gift from Kevin Jones (Dept. of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO, USA) (Baquet et al., 2005; Gorski et al., 2003a,b).”

“BDNF may function similarly in other BDNF-dependent sensory populations (Brady et al., 1999; ElShamy and Ernfors, 1997; Erickson et al., 2001; Ernfors, 2001); however, geniculate neurons are the first BDNF-dependent sensory population in which neuron proliferation and death have been specifically examined.”

“5 (White et al., 1996).”

“Neurofilaments are typically expressed in differentiated neurons, but can also be expressed in late stage neuronal precursors (Hall and Landis, 1991; Tapscott et al., 1981).”

“BDNF may function similarly in other BDNF-dependent sensory populations (Brady et al., 1999; ElShamy and Ernfors, 1997; Erickson et al., 2001; Ernfors, 2001); however, geniculate neurons are the first BDNF-dependent sensory population in which neuron proliferation and death have been specifically examined.”

“At later embryonic ages, BDNF expression in the fungiform papillae decreases (Nosrat and Olson, 1995), resulting in neuronal death by the activation of both Bax and caspase-3.”

“These neurotrophins are sometimes thought to be produced by peripheral target tissues, where they influence neuron number by preventing the death of ganglion neurons that innervate them (Huang and Reichardt, 2001; Vogel and Davies, 1991).”

“This approach has been used successfully to examine changes in ganglion neuron number followingmanipulations of neurotrophins (Agerman et al., 2003; ElShamy and Ernfors, 1997; Erickson et al., 2001, 1996).”

“Bdnf-lacZ mice have been used successfully to examine BDNF-producing locations in the adult taste system (Yee et al., 2003).”

“The initial vestibular and visceral BDNF-dependent sensory neuron loss occurs well after, rather than concurrent with, target innervation in bdnf−/− mice (Brady et al., 1999; ElShamy and Ernfors, 1997; Erickson et al., 2001; Ernfors, 2001).”

“Neurotrophins have been shown to influence the survival of both neuronal precursors and differentiated neurons (Ernfors, 2001; Farinas et al., 2002; Liebl et al., 2000; LopezSanchez and Frade, 2002).”

“This finding is consistent with previous demonstrations that Bax-null mutation rescues BDNF-dependent neuronal loss in the developing nodosepetrosal ganglion as well as in the visceral ganglion (Hellard et al., 2004).”

“Thus, caspase-3 acts as a relevant marker for developmental cell death (De Zio et al., 2005).”

“Neurotrophins have been shown to influence the survival of both neuronal precursors and differentiated neurons (Ernfors, 2001; Farinas et al., 2002; Liebl et al., 2000; LopezSanchez and Frade, 2002).”

“BDNF may function similarly in other BDNF-dependent sensory populations (Brady et al., 1999; ElShamy and Ernfors, 1997; Erickson et al., 2001; Ernfors, 2001); however, geniculate neurons are the first BDNF-dependent sensory population in which neuron proliferation and death have been specifically examined.”

“geniculate neurons (Nosrat, 1998; Nosrat et al., 1996; Nosrat and Olson, 1995; Schecterson and Bothwell, 1992), the removal of BDNF frommultiple locations, at any embryonic age and through a variety of mechanisms could result in a reduction of geniculate neurons.”

“The development of peripheral circuitry in the taste system is highly regulated, in that each taste bud is innervated by a specific number of neurons (Krimm and Hill, 1998; Zaidi and Whitehead, 2006).”

“6C,F), an intermediate filament found specifically in neurons (Debus et al., 1982; Shaw et al., 1984).”

“Approximately 45–65% of the taste buds on the anterior tongue, whose survival requires gustatory innervation, are also lost in bdnf−/−mice (Mistretta et al., 1999; Nosrat et al., 1997; Sun and Oakley, 2002), indicating that many of the missing neurons are gustatory.”

“…not only regulate neuronal numbers by influencing survival of differentiated neurons, but can also influence survival, differentiation, and proliferation of neuronal precursors during early development (Ernfors, 2001; Farinas et al., 2002; Liebl et al., 2000; Lopez-Sanchez and Frade, 2002).”

“6C,F), an intermediate filament found specifically in neurons (Debus et al., 1982; Shaw et al., 1984).”

“5–E13 in mouse), cell proliferation has slowed and thereafter the total number of neurons remains constant throughout the embryonic period (Carr et al., 2005).”

“BDNF is required to maintain embryonic geniculate neuron number in vivo and in vitro (Al-Hadlaq et al., 2003; Conover et al., 1995).”

“5 (Mbiene, 2004).”

“…in cell loss of neurons in the sensory ganglia, including the vestibular ganglion (Bianchi et al. 1996), dorsal root ganglia, trigeminal ganglia (Ernfors et al. 1994), geniculate ganglia of the facial nerve (Patel and Krimm 2010) and the cranial and spinal sensory ganglia (Jones et al. 1994).”

“Notably, the UC-MSCs produced higher levels of BDNF (13,900±2156 pg/ml), which can enhance the growth, differentiation and survival of neurons (34) This suggested additional potential applications for UC-CM.”

“…bind specifically to the cleaved fragment of capase-3 and not to the full-length protein by western blot (Cheong et al, 2003; Garnier et al, 2003; Thome et al, 2012), as well as being validated for use with paraffin-embedded immunohistochemistry (Gown and Willingham, 2002; Patel and Krimm, 2010).”

“C-fos may regulate expression of BDNF [41, 64], and BDNF could play key roles in survival, differentiation and synaptic plasticity of neurons [69].”

“Use of this antibody for immunohistochemistry has been previously described in rodents [29] and chicken [30].”

“broadly expressed TrkB receptor involved in GG survival (24), we examined TuJ1, Brn3a, and TrkB expression, followed by quantification of the proportion of each subgroup.”

“5 (Patel and Krimm, 2010), at E11.”

“Both antibodies have been established in the literature for this purpose (Guagliardo & Hill, 2007; Meng, Huang, Sun, Hill, & Krimm, 2017; Meng, Ohman-Gault, Ma, & Krimm, 2015; Patel & Krimm, 2010; Rutlin et al., 2014).”

“Even during development, only approximately half of the gustatory neurons are dependent on BDNF (Patel and Krimm, 2010), and there is a subpopulation of taste neurons that do not express the BDNF receptor, TrkB, and are not dependent on TrkB during development (Fei and Krimm, 2013).”

“Many neurotrophin knockout studies have demonstrated a loss of taste buds at birth due to the earlier loss of geniculate neurons [3,6,7,12,13,15,21].”

“As p75 also binds BDNF and NT4, it is possible that this receptor could mediate BDNF and This is an Open Access article distributed under the terms of the Creative ommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and iginal work is properly credited.”

“…receptor (TrkB) globally during early development dramatically decreases the normal numbers of taste buds and the number of neurons surviving to adulthood (Fritzsch et al., 1997; Nosrat et al., 1997; Zhang et al., 1997; Oakley et al., 1998; Oakley, 1998; Patel and Krimm, 2010; Patel et al., 2010).”

“…all of the following 1) factors that regulate cell death/survival, because BDNF and NT4 are still supporting geniculate neuron survival at this age (Patel and Krimm, 2010, 2012); 2) factors that regulate axon guidance and target innervation, because chorda tympani axons are first innervating their…”

“action of target-derived BDNF on geniculate neurons (Patel and Krimm, 2010).”

“Deletion of Bdnf or NT-4, which acts primarily through TrkB receptors, affects distinct aspects of gustatory system development according to their different spatio-temporal expression patterns [2,5,6].”

“BDNF mRNA is expressed in early developing taste papillae and is essential during embryonic initiation and the maintenance of gustatory innervation of taste buds (19-22).”

“BDNF regulates the number of neurons in the developing geniculate ganglion by preventing cell death instead of promoting cell proliferation (Patel and Krimm, 2010) [43].”

“After this embryonic critical period, geniculate neurons do not depend on BDNF for survival (Hoshino, Vatterott, Egwiekhor, & Rochlin, 2010; Patel & Krimm, 2010).”

“…of peripheral connections are highly regulated by BDNF and NT-4 and its receptors (Fritzsch et al., 1997; Zhang et al., 1997; Krimm et al., 2001; Lopez and Krimm, 2006b; Ma et al., 2009; Patel et al., 2010; Patel and Krimm, 2010; Fei and Krimm, 2013; Fei et al., 2014; Huang and Krimm, 2014).”

“5 in mice (Patel and Krimm, 2010).”